Substituted thieno [2,3-d] pyrimidines as HIV inhibitors

ABSTRACT

This application concerns certain 4-cyanophenylamino-substituted bicyclic heterocycles of formula I 
                         
where the dashed line represents a double bond that may be located either between A and C(V) or between C(V) and D, where A is S or C(Z); D is S or C(W); provided that one and only one of A and D is S; where T is NH, O, or S; and where other substituents are defined herein. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.

CROSS-REFERENCE

This application is a divisional of a U.S. application Ser. No.12/504,566, filed Jul. 16, 2009, now U.S. Pat. No. 8,211,898 which is adivisional of U.S. application Ser. No. 11/938,101, filed Nov. 9, 2007,which issued as U.S. Pat. No. 7,595,324 on Sep. 29, 2009, and whichclaims the benefit of U.S. Provisional Application No. 60/858,082, filedNov. 9, 2006, each of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

Human Immunodeficiency Virus (HIV) presents a public-health and socialcatastrophe too well known to require documentation. One therapeuticapproach to HIV has been inhibition of the viral RNA-dependent RNApolymerase; this enzyme is frequently referred to as “reversetranscriptase,” abbreviated “RT.” The first RT inhibitors werenucleoside analogs such as AZT and ddI. Although such nucleoside RTinhibitors were frequently effective against the wild-type virus, anysingle-drug treatment has been hobbled by the virus's ability to readilyproduce drug-resistant mutants. This has lead to an intense search fornon-nucleoside RT inhibitors (“NNRTIs”), which are both effective andcapable of retaining their effectiveness despite drug-resistancemutations. A recent review of NNRTIs can be found in Balzarni, J., 2004,Cur. Top. Med. Chem. 4, 921-44 (Erratum ibid. 4, 1825).

Four leading NNRTI are: 1) Efavirenz (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one; 2) Capravirine: 1H-Imidazole-2-methanol,5-((3,5-dichlorophenyl)thio)-4-(1-methylethyl)-1-(4-pyridinylmethyl)-carbamate(ester); 3) Etravirine (TMC 125):4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl)oxy)-3,5-dimethyl-benzonitrile; and 4) Rilpivirine (TMC-278):4-([4-[(4-[(/E)-2-cyanoethenyl]-2,6-dimethylphenyl)amino]-2-pyrimidinyl)amino]benzonitrile. Rilpivirine and Etravirine belong to asubclass of NNRTIs called diarylpyrmidines (“DAPY”). For a review ofthese DAPY NNRTIs see Ludovici, D. W., et al., 2002, Bioorg. Med. Chem.Lett. 11, 2235-9. An extensive patent literature also exists for DAPY.U.S. Pat. No. 6,197,779; WO 00/27850; WO 2003/016306; and WO2004/069812, all of which are assigned to Janssen Pharmaceuticals.

Diaryl compounds similar to Etravirine and Rilpivirine where thepyrimidine moiety is replaced by a purine are described in WO2005/028479, which also is assigned to Janssen.

SUMMARY OF THE INVENTION

The invention provides compounds of formula I:

where the dashed line represents a double bond that may be locatedeither between A and C(V) or between C(V) and D;

A is S or C(Z);

D is S or C(W);

-   -   provided that one and only one of A and D is S;

T is NH, O, or S;

W and Z are, independently, H, F, Cl, Br, C₁-C₆ alkyl; C₂-C₆ alkenyl;OC₁-C₆ alkyl; C₃-C₆ cycloalkyl; OC₃-C₆ cycloalkyl, phenyl, or benzyl,wherein alkyl, alkenyl, cycloalkyl, and phenyl groups and the phenylmoiety of the benzyl group are optionally substituted with 1-3 groupsselected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃ alkyl

V is H, halogen, C₁-C₆ alkyl;

-   -   or V and W, together with the ring atoms to which they are        attached, form an additional, fused 5-, 6-, or 7-membered ring,        optionally containing one or two heteroatoms, which additional        ring may be saturated, unsaturated, or aromatic;    -   or V and Z, together with the ring atoms to which they are        attached, form an additional, fused 5-, 6-, or 7-membered ring,        optionally containing one or two heteroatoms, which additional        ring may be saturated, unsaturated, or aromatic;

Ar is selected from (a), (b), (c), and (d) below:

wherein

-   -   each R^(P) is selected from among methyl, ethyl, propyl,        isopropyl, cyclopropylmethyl, or C₃-C₆ cycloalkyl, cyano,        CH═CHCN, Cl, Br, I, acetyl, and C₁-C₆ alkyl-NH;    -   R⁴, R⁵ and each R⁶ are independently selected from H, F, Cl, Br,        CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,        NH₂, and NHCH₃, or    -   R⁶ and R^(P) on adjacent ring atoms, together with the ring        atoms to which they are attached, form an additional fused        five-membered ring;    -   Q and Q′ are independently selected from N and CH;    -   R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl,        t-butyl, or cyclobutyl; and    -   R⁸-R¹¹ are, independently, H or CH₃;        or a pharmaceutically acceptable salt, solvate, hydrate,        polymorph, ester., tautomer or prodrug thereof.

In one generic embodiment this invention provides a compound of formulaIA, in which the 6-linker T in formula I is T′, which may be O or S.

In one subgeneric embodiment, the invention provides or contemplates acompound of formula IA where Ar is selected from 2-chloro-4-cyclopropylphenyl; 2-methyl-4-cyclopropyl-naphth-1-yl; 2,6-dimethyl-4-cyanophenyl;2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl;2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl;2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropylphenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.

In another subgeneric embodiment, the invention contemplates a compoundof formula IA where Ar is selected from the following:5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl;5-cyclopropyl-7-trifluoromethyl-8-quinolyl; 5-acetyl-8-quinolyl;5-cyano-7-methoxy-8-quinolyl; 5-cyano-7-methyl-8-quinolyl;5-cyclopropyl-7-trifluoromethoxy-8-isoquinolyl; 5-cyano-8-isoquinolyl;5-cyano-7-methoxy-8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl;5-cyclobutyl-7-difluoromethyl-8-isoquinolyl; 5,7-dimethyl-8-cinnolyl;5-cyclopropyl-7-methyl-8-cinnolyl; and5-(2-cyanoethenyl)-7-methyl-8-cinnolyl.

In another subgeneric embodiment, the invention provides a compound offormula IA-1

where Ar, V, and Z are defined as for formula I.

In another subgeneric embodiment, the invention provides a compound offormula IA-2

where Ar, V, and W are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IA-3

where Ar, V and Z are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IA-4

where Ar, V and W are defined as for formula I.

In another generic embodiment, this invention provides a compound offormula IB

where all substituents are as described above.

In one subgeneric embodiment, the invention provides a compound offormula IB where Ar is (c).

In a more specific subgeneric embodiment, the invention provides acompound of formula IB where Ar is

where RP is CN, CH═CHCN, or cyclopropyl; where R⁶ and R⁷ are either bothmethyl or both methoxy.

In another subgeneric embodiment, this invention provides a compound offormula IB-1.

where Ar, V and W are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IB-2.

where Ar, V and Z are as described above for formula I.

In more specific embodiments, the invention provides compounds of any ofIA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (a).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (b).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (c).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (d).

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, IA-2, IA-3, or IA-4, whereAr is 2,6-disubstituted-4-cyclopropyl, 2,6-disubstituted-4-acetyl,2,4,6-trimethyl, 2,6-disubstituted-4-bromo, or4-cyano-2,6-di-substituted phenyl.

In a still more specific subgeneric embodiment, this invention providesor contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4, where Aris 4-cyano-2,6-di-methoxy phenyl or 4-cyano-2,6-di-methyl phenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where V is H, halo, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, phenyl, or benzyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-1, IA-2, IA-3, orIA-4, where A is S and W is H, C₃-C₆ cycloalkyl, or 0C₃-C₆ cycloalkyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, unsubstituted C₁-C₄ alkyl, monosubstitutedC₁-C₄ alkyl, or C₂-C₃ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, halo, halomethyl, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and V and W, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered carbocyclicring.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and V and W, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7- membered ring, whichring contains one or two heteroatoms selected from 0, N, and S.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, C₁-C₆ alkyl, or C₂-C₆ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, C₃-C₆ cycloalkyl, or 0C₃-C₆ cycloalkyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, unsubstituted C₁-C₄ alkyl, monosubstitutedC₁-C₄ alkyl, or C₂-C₃ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, halo, halomethyl, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-1, IA-2, IA-3, orIA-4, where D is S and Z is H, phenyl, or benzyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and V and Z, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7- membered carbocyclicring.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and V and Z, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered ring, whichring contains one or two heteroatoms selected from O, N, and S.

In a preferred embodiment, the invention provides for compounds offormula I and their pharmaceutically acceptable salts.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable solvates.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable hydrates.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable polymorphs.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable esters.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable tautomers.

In further or additional embodiments, the invention provides forcompounds of formula I and their pharmaceutically acceptable prodrugs.

The compounds described herein have inhibitory activity against bothwild-type and mutated forms of human immunodeficiency virus type 1(HIV-1).

Described herein are pharmaceutical compositions comprising a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof. In some embodiments, thepharmaceutical compositions further comprise a pharmaceuticallyacceptable carrier. Such compositions may contain adjuvants, excipients,preservatives, agents for delaying absorption, fillers, binders,adsorbents, buffers, disintegrating agents, solubilizing agents, othercarriers, and other inert ingredients. Methods of formulation of suchcompositions are well-known in the art.

In some embodiments, the pharmaceutical composition is in a formsuitable for oral administration. In further or additional embodiments,the pharmaceutical composition is in the form of a tablet, capsule,pill, powder, sustained release formulation, solution, suspension, forparenteral injection as a sterile solution, suspension or emulsion, fortopical administration as an ointment or cream or for rectaladministration as a suppository. In further or additional embodiments,the pharmaceutical composition is in unit dosage forms suitable forsingle administration of precise dosages. In further or additionalembodiments the amount of compound of formula I is in the range of about0.001 to about 1000 mg/kg body weight/day. In further or additionalembodiments the amount of compound of formula I is in the range of about0.5 to about 50 mg/kg/day. In further or additional embodiments theamount of compound of formula I is about 0.001 to about 7 g/day. Infurther or additional embodiments the amount of compound of formula I isabout 0.002 to about 6 g/day. In further or additional embodiments theamount of compound of formula I is about 0.005 to about 5 g/day. Infurther or additional embodiments the amount of compound of formula I isabout 0.01 to about 5 g/day. In further or additional embodiments theamount of compound of formula I is about 0.02 to about 5 g/day. Infurther or additional embodiments the amount of compound of formula I isabout 0.05 to about 2.5 g/day. In further or additional embodiments theamount of compound of formula I is about 0.1 to about 1 g/day. Infurther or additional embodiments, dosage levels below the lower limitof the aforesaid range may be more than adequate. In further oradditional embodiments, dosage levels above the upper limit of theaforesaid range may be required. In further or additional embodimentsthe compound of formula I is administered in a single dose, once daily.In further or additional embodiments the compound of formula I isadministered in multiple doses, more than once per day. In further oradditional embodiments the compound of formula I is administered twicedaily. In further or additional embodiments the compound of formula I isadministered three times per day. In further or additional embodimentsthe compound of formula I is administered four times per day. In furtheror additional embodiments the compound of formula I is administered morethan four times per day. In some embodiments, the pharmaceuticalcomposition is for administration to a mammal. In further or additionalembodiments, the mammal is human. In further or additional embodiments,the pharmaceutical composition further comprises a pharmaceuticalcarrier, excipient and/or adjuvant. In further or additionalembodiments, the pharmaceutical composition further comprises at leastone therapeutic agent In further or additional embodiments, thetherapeutic agent is an HIV or AIDS drug, or a drug for the treatment ofthe symptoms of HIV or AIDS. . In further or additional embodiments, thepharmaceutical composition is administered in combination with anadditional therapy. In further or additional embodiments, thepharmaceutical composition comprises a pharmaceutically acceptable saltof a compound of formula I.

Also described herein are methods for inhibiting a reverse transcriptaseenzyme. In some embodiments, the method comprises contacting saidreverse transcriptase enzyme with an amount of a composition comprisinga compound of formula I or a pharmaceutically acceptable salt, solvate,polymorph, ester, tautomer or prodrug thereof, sufficient to inhibitsaid enzyme, wherein said enzyme is inhibited. In further or additionalembodiments the enzyme is at least about 1% inhibited. In further oradditional embodiments the enzyme is at least about 2% inhibited. Infurther or additional embodiments the enzyme is at least about 3%inhibited. In further or additional embodiments the enzyme is at leastabout 4% inhibited. In further or additional embodiments the enzyme isat least about 5% inhibited. In further or additional embodiments theenzyme is at least about 10% inhibited. In further or additionalembodiments the enzyme is at least about 20% inhibited. In further oradditional embodiments the enzyme is at least about 25% inhibited. Infurther or additional embodiments the enzyme is at least about 30%inhibited. In further or additional embodiments the enzyme is at leastabout 40% inhibited. In further or additional embodiments the enzyme isat least about 50% inhibited. In further or additional embodiments theenzyme is at least about 60% inhibited. In further or additionalembodiments the enzyme is at least about 70% inhibited. In further oradditional embodiments the enzyme is at least about 75% inhibited. Infurther or additional embodiments the enzyme is at least about 80%inhibited. In further or additional embodiments the enzyme is at leastabout 90% inhibited. In further or additional embodiments the enzyme isessentially completely inhibited. In further or additional embodimentsthe reverse transcriptase enzyme is HIV reverse transcriptase. Infurther or additional embodiments the reverse transcriptase enzyme isHIV-1 reverse transcriptase. In further or additional embodiments theHIV reverse transcriptase is resistant to non-nucleoside reversetranscriptase inhibitors. In further or additional embodiments thecontacting occurs within a cell. In further or additional embodimentsthe cell is a mammalian cell. In further or additional embodiments themammalian cell is a human cell. In further or additional embodiments thecontacting occurs in vitro. In further or additional embodiments thecontacting occurs in vivo. In further or additional embodiments thecontacting occurs within the body of a subject infected with HIV. Infurther or additional embodiments, the reverse transcriptase enzyme isinhibited with a composition comprising a pharmaceutically acceptablesalt of a compound of formula I.

Also described herein are methods of treating or preventing a disease inan individual comprising administering to said individual an effectiveamount of a compound of formula I or a composition comprising a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof. In further or additionalembodiments, the disease is HIV. In further or additional embodiments,the disease is AIDS. In further or additional embodiments, the diseaseis ARC.

Also described herein are compounds that inhibit the replication of HIV,including drug resistant strains of the virus. Accordingly, the presentinvention provides pharmaceutical compositions, and prophylactic andtherapeutic treatments, diagnostic and prognostic methods and kits, andpharmaceutical screening methods that take advantage of the anti-HIVactivity of these compounds and compositions. Compounds that inhibit HIVreplication are candidates for the prophylactic or therapeutic treatmentof HIV infection. Prophylactic treatments are especially useful forpersons at high risk of HIV infection.

Also described herein are compositions comprising at least one compoundof formula I and a second therapeutic agent or agents. In someembodiments, the second therapeutic agent is used to prevent or treatHIV infection. In further or additional embodiments, the secondtherapeutic agent is used to treat an opportunistic infection associatedwith HIV infection. The second therapeutic is, for example, a proteaseinhibitor, a non-nucleoside reverse transcriptase inhibitor, anucleoside reverse transcriptase inhibitor, an antiretroviralnucleoside, an entry inhibitor, or any other anti-viral agent effectiveto inhibit or treat HIV infection. In further or additional embodiments,the second therapeutic agent is selected from the group consisting ofzidovudine, didanosine, stavudine, interferon, lamivudine, adefovir,nevirapine, delaviridine, loviride, saquinavir, indinavir, and AZT. Infurther or additional embodiments, the second therapeutic agent is anantibiotic or acyclovir. In still a further embodiment, the second agentis selected from immunomodulators, and entry inhibitors.

Also described herein are methods of inhibiting HW replication in aperson by administering to the person a pharmaceutically effectiveamount of at least one compound of formula I. Further described hereinare methods of treating or preventing HIV infection in a subjectcomprising administering compound of formula Ito a subject. Thecompounds described herein can be administered orally, parentally(including subcutaneous injection, intravenous, intramuscular,intrasternal or infusion techniques), by inhalation spray, topically, byabsorption through a mucous membrane, or rectally, in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants or vehicles.

Also described herein are methods for inhibiting the replication of drugresistant, including multi-drug resistant, HIV mutants, comprisingadministering at least one compound of formula I. The compounds of theinvention are potent against HIV and drug resistant strains of HW.

In another aspect, the present invention provides methods of inhibitingHIV infection in a CD4 culture comprising contacting the cell at leastone compound of formula I, either alone or in combination with a secondtherapeutic agent or a combination of other therapeutic agents. In someembodiments, the therapeutic agent or agents are used to treat orprevent HIV infection.

The present invention provides new compositions and methods forpreventing or ameliorating viral, e.g., HW infection, killing virallyinfected cells, e.g., HW infected cells and generally, inhibiting viral,preferably HIV, replication. The compounds described herein effectivelyinhibit HIV infection, kill HIV infected cells and/or prevent HIVinfection in the individual. Moreover, the compounds of the inventioninhibit the replication of drug resistant strains of HIV.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. All patents, patentapplications, published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there is a plurality of definitionsfor terms herein, those in this section prevail. Where reference is madeto a URL or other such identifier or address, it is understood that suchidentifiers can change and particular information on the internet cancome and go, but equivalent information can be found by searching theinternet or other appropriate reference source. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. It should alsobe noted that use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes”, and “included” is not limiting.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, IR andUV/Vis spectroscopy and pharmacology, within the skill of the art areemployed. Unless specific definitions are provided, the nomenclatureemployed in connection with, and the laboratory procedures andtechniques of, analytical chemistry, synthetic organic chemistry, andmedicinal and pharmaceutical chemistry described herein are those knownin the art. Standard techniques can be used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients. Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods well known in the art and as describedin various general and more specific references that are cited anddiscussed throughout the present specification. Throughout thespecification, groups and substituents thereof can be chosen by oneskilled in the field to provide stable moieties and compounds.

Where substituent groups are specified by their conventional chemicalformulas, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left. As a non-limiting example, —CH₂O— isequivalent to —OCH₂—.

Unless otherwise noted, the use of general chemical terms, such asthough not limited to “alkyl,” “amine,” “aryl,” are equivalent to theiroptionally substituted forms. For example, “alkyl,” as used herein,includes optionally substituted alkyl.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration, or combinationsthereof. Likewise, the compounds presented herein may possess one ormore double bonds and each may exist in the E (trans) or Z (cis)configuration, or combinations thereof. Presentation of one particularstereoisomer, regioisomer, diastereomer, enantiomer or epimer should beunderstood to include all possible stereoisomers, regioisomers,diastereomers, enantiomers or epimers and mixtures thereof. Thus, thecompounds presented herein include all separate configurationalstereoisomeric, regioisomeric, diastereomeric, enantiomeric, andepimeric forms as well as the corresponding mixtures thereof. Techniquesfor inverting or leaving unchanged a particular stereocenter, and thosefor resolving mixtures of stereoisomers are well known in the art and itis well within the ability of one of skill in the art to choose anappropriate method for a particular situation. See, for example, Furnisset al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.

The terms “moiety”, “chemical moiety”, “group” and “chemical group”, asused herein refer to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “catalytic group” refers to a chemical functional group thatassists catalysis by acting to lower the activation barrier to reaction.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined below.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons (except in those instances where macromolecular substituents areclearly intended, e.g., polypeptides, polysaccharides, polyethyleneglycols, DNA, RNA and the like).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as theranges C₁-C₂ and C₁-C₃. Thus, by way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl group,i.e., the alkyl group is selected from among methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g. ,“1 to 10 carbon atoms” means that thegroup may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9carbon atoms, or 10 carbon atoms.

The term “hydrocarbon” as used herein, alone or in combination, refersto a compound or chemical group containing only carbon and hydrogenatoms.

The terms “heteroatom” or “hetero” as used herein, alone or incombination, refer to an atom other than carbon or hydrogen. Heteroatomsare may be independently selected from among oxygen, nitrogen, sulfur,phosphorous, silicon, selenium and tin but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can be the same as each another, or some or allof the two or more heteroatoms can each be different from the others.

The term “alkyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain saturated hydrocarbon monoradical having from one toabout ten carbon atoms, more preferably one to six carbon atoms.Examples include, but are not limited to methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated.

The term “alkylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, alkyl. Examplesinclude, but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), isopropylene (—CH(CH₃)CH₂—) and the like.

The term “alkenyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbondouble-bonds and having from two to about ten carbon atoms, morepreferably two to about six carbon atoms. The group may be in either thecis or trans conformation about the double bond(s), and should beunderstood to include both isomers. Examples include, but are notlimited to ethenyl (—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl[—C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like. Whenever it appearsherein, a numerical range such as “C₂-C₆ alkenyl” or “C₂₋₆ alkenyl”,means that the alkenyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkenyl”where no numerical range is designated.

The term “alkenylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical alkenyl. Examplesinclude, but are not limited to ethenylene (—CH═CH—), the propenyleneisomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

The term “alkynyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbontriple-bonds and having from two to about ten carbon atoms, morepreferably from two to about six carbon atoms. Examples include, but arenot limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and thelike. Whenever it appears herein, a numerical range such as “C₂-C₆alkynyl” or “C₂₋₆ alkynyl”, means that the alkynyl group may consist of2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrenceof the term “alkynyl” where no numerical range is designated.

The term “alkynylene” as used herein, alone or in combination, refers toa diradical derived from the above-defined monoradical, alkynyl.Examples include, but are not limited to ethynylene (—C≡C—),propargylene (—CH₂—C≡C—) and the like.

The term “aliphatic” as used herein, alone or in combination, refers toan optionally substituted, straight-chain or branched-chain, non-cyclic,saturated, partially unsaturated, or fully unsaturated nonaromatichydrocarbon. Thus, the term collectively includes alkyl, alkenyl andalkynyl groups.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” as usedherein, alone or in combination, refer to optionally substituted alkyl,alkenyl and alkynyl structures respectively, as described above, inwhich one or more of the skeletal chain carbon atoms (and any associatedhydrogen atoms, as appropriate) are each independently replaced with aheteroatom (i.e. an atom other than carbon, such as though not limitedto oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinationsthereof), or heteroatomic group such as though not limited to —O—O—,—S—S—, —O—S—, —S—O—, ═N—N═, —N═N—, —N═N—NH—, —P(O)₂—, —O—P(O)₂—,—P(O)₂—O—, —S(O)—, —S(O)₂—, —SnH₂— and the like.

The terms “haloalkyl”, “haloalkenyl” and “haloalkynyl” as used herein,alone or in combination, refer to optionally substituted alkyl, alkenyland alkynyl groups respectively, as defined above, in which one or morehydrogen atoms is replaced by fluorine, chlorine, bromine or iodineatoms, or combinations thereof. In some embodiments two or more hydrogenatoms may be replaced with halogen atoms that are the same as eachanother (e.g. difluoromethyl); in other embodiments two or more hydrogenatoms may be replaced with halogen atoms that are not all the same aseach other (e.g. 1-chloro-1-fluoro-1 -iodoethyl). Non-limiting examplesof haloalkyl groups are fluoromethyl and bromoethyl. A non-limitingexample of a haloalkenyl group is bromoethenyl. A non-limiting exampleof a haloalkynyl group is chloroethynyl.

The term “perhalo” as used herein, alone or in combination, refers togroups in which all of the hydrogen atoms are replaced by fluorines,chlorines, bromines, iodines, or combinations thereof. Thus, as anon-limiting example, the term “perhaloalkyl” refers to an alkyl group,as defined herein, in which all of the H atoms have been replaced byfluorines, chlorines, bromines or iodines, or combinations thereof. Anon-limiting example of a perhaloalkyl group isbromo,chloro,fluoromethyl. A non-limiting example of a perhaloalkenylgroup is trichloroethenyl. A non-limiting example of a perhaloalkynylgroup is tribromopropynyl.

The term “carbon chain” as used herein, alone or in combination, refersto any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl orheteroalkynyl group, which is linear, cyclic, or any combinationthereof. If the chain is part of a linker and that linker comprises oneor more rings as part of the core backbone, for purposes of calculatingchain length, the “chain” only includes those carbon atoms that composethe bottom or top of a given ring and not both, and where the top andbottom of the ring(s) are not equivalent in length, the shorter distanceshall be used in determining the chain length. If the chain containsheteroatoms as part of the backbone, those atoms are not calculated aspart of the carbon chain length.

The terms “cycle”, “cyclic”, “ring” and “membered ring” as used herein,alone or in combination, refer to any covalently closed structure,including alicyclic, heterocyclic, aromatic, heteroaromatic andpolycyclic fused or non-fused ring systems as described herein. Ringscan be optionally substituted. Rings can form part of a fused ringsystem. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, by way of example only,cyclohexane, pyridine, pyran and pyrimidine are six-membered rings andcyclopentane, pyrrole, tetrahydrofuran and thiophene are five-memberedrings.

The term “fused” as used herein, alone or in combination, refers tocyclic structures in which two or more rings share one or more bonds.

The term “cycloalkyl” as used herein, alone or in combination, refers toan optionally substituted, saturated, hydrocarbon monoradical ring,containing from three to about fifteen ring carbon atoms or from threeto about ten ring carbon atoms, though may include additional, non-ringcarbon atoms as substituents (e.g. methylcyclopropyl). Whenever itappears herein, a numerical range such as “C₃-C₆ cycloalkyl ” or “C₃₋₆cycloalkyl”, means that the cycloalkyl group may consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., iscyclopropyl, cyclobutyl, cyclopentyl or cyclohepty, although the presentdefinition also covers the occurrence of the term “cycloalkyl” where nonumerical range is designated. The term includes fused, non-fused,bridged and spiro radicals. A fused cycloalkyl may contain from two tofour fused rings where the ring of attachment is a cycloalkyl ring, andthe other individual rings may be alicyclic, heterocyclic, aromatic,heteroaromatic or any combination thereof. Examples include, but are notlimited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo[2.2.1] heptyl and adamantyl ring systems. Illustrative examplesinclude, but are not limited to the following moieties:

and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an optionally substituted hydrocarbon non-aromatic, monoradical ring,having one or more carbon-carbon double-bonds and from three to abouttwenty ring carbon atoms, three to about twelve ring carbon atoms, orfrom three to about ten ring carbon atoms. The term includes fused,non-fused, bridged and spiro radicals. A fused cycloalkenyl may containfrom two to four fused rings where the ring of attachment is acycloalkenyl ring, and the other individual rings may be alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof. Fusedring systems may be fused across a bond that is a carbon-carbon singlebond or a carbon-carbon double bond. Examples of cycloalkenyls include,but are not limited to cyclohexenyl, cyclopentadienyl andbicyclo[2.2.1]hept-2-ene ring systems. Illustrative examples include,but are not limited to the following moieties:

and the like.

The terms “alicyclyl” or “alicyclic” as used herein, alone or incombination, refer to an optionally substituted, saturated, partiallyunsaturated, or fully unsaturated nonaromatic hydrocarbon ring systemscontaining from three to about twenty ring carbon atoms, three to abouttwelve ring carbon atoms, or from three to about ten ring carbon atoms.Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.

The terms “non-aromatic heterocyclyl” and “heteroalicyclyl” as usedherein, alone or in combination, refer to optionally substituted,saturated, partially unsaturated, or fully unsaturated nonaromatic ringmonoradicals containing from three to about twenty ring atoms, where oneor more of the ring atoms are an atom other than carbon, independentlyselected from among oxygen, nitrogen, sulfur, phosphorous, silicon,selenium and tin but are not limited to these atoms. In embodiments inwhich two or more heteroatoms are present in the ring, the two or moreheteroatoms can be the same as each another, or some or all of the twoor more heteroatoms can each be different from the others. The termsinclude fused, non-fused, bridged and spiro radicals. A fusednon-aromatic heterocyclic radical may contain from two to four fusedrings where the attaching ring is a non-aromatic heterocycle, and theother individual rings may be alicyclic, heterocyclic, aromatic,heteroaromatic or any combination thereof. Fused ring systems may befused across a single bond or a double bond, as well as across bondsthat are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.The terms also include radicals having from three to about twelveskeletal ring atoms, as well as those having from three to about tenskeletal ring atoms. Attachment of a non-aromatic heterocyclic subunitto its parent molecule can be via a heteroatom or a carbon atom.Likewise, additional substitution can be via a heteroatom or a carbonatom. As a non-limiting example, an imidazolidine non-aromaticheterocycle may be attached to a parent molecule via either of its Natoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbonatoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl). Incertain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples include, but are not limited topyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl and quinolizinyl. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like. The terms also include all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “aromatic” as used herein, refers to a planar, cyclic orpolycyclic, ring moiety having a delocalizedπ-electron system containing4n+2π electrons, where n is an integer. Aromatic rings can be formed byfive, six, seven, eight, nine, or more than nine atoms. Aromatics can beoptionally substituted and can be monocyclic or fused-ring polycyclic.The term aromatic encompasses both all carbon containing rings (e.g.,phenyl) and those rings containing one or more heteroatoms (e.g.,pyridine).

The term “aryl” as used herein, alone or in combination, refers to anoptionally substituted aromatic hydrocarbon radical of six to abouttwenty ring carbon atoms, and includes fused and non-fused aryl rings. Afused aryl ring radical contains from two to four fused rings where thering of attachment is an aryl ring, and the other individual rings maybe alicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Further, the term aryl includes fused and non-fused ringscontaining from six to about twelve ring carbon atoms, as well as thosecontaining from six to about ten ring carbon atoms. A non-limitingexample of a single ring aryl group includes phenyl; a fused ring arylgroup includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and anon-fused bi-aryl group includes biphenyl.

The term “arylene” as used herein, alone or in combination, refers to adiradical derived from the above-defined monoradical, aryl. Examplesinclude, but are not limited to 1, 2-phenylene, 1,3-phenylene,1,4-phenylene, 1,2-naphthylene and the like.

The term “heteroaryl” as used herein, alone or in combination, refers tooptionally substituted aromatic monoradicals containing from about fiveto about twenty skeletal ring atoms, where one or more of the ring atomsis a heteroatom independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but not limited to theseatoms and with the proviso that the ring of said group does not containtwo adjacent O or S atoms. In embodiments in which two or moreheteroatoms are present in the ring, the two or more heteroatoms can bethe same as each another, or some or all of the two or more heteroatomscan each be different from the others. The term heteroaryl includesoptionally substituted fused and non-fused heteroaryl radicals having atleast one heteroatom. The term heteroaryl also includes fused andnon-fused heteroaryls having from five to about twelve skeletal ringatoms, as well as those having from five to about ten skeletal ringatoms. Bonding to a heteroaryl group can be via a carbon atom or aheteroatom. Thus, as a non-limiting example, an imidiazole group may beattached to a parent molecule via any of its carbon atoms(imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms(imidazol-1-yl or imidazol-3-yl). Likewise, a heteroaryl group may befurther substituted via any or all of its carbon atoms, and/or any orall of its heteroatoms. A fused heteroaryl radical may contain from twoto four fused rings where the ring of attachment is a heteroaromaticring and the other individual rings may be alicyclic, heterocyclic,aromatic, heteroaromatic or any combination thereof. A non-limitingexample of a single ring heteroaryl group includes pyridyl; fused ringheteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and anon-fused bi-heteroaryl group includes bipyridinyl. Further examples ofheteroaryls include, without limitation, furanyl, thienyl, oxazolyl,acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl,benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl,indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl,pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl,purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl,quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyland the like, and their oxides, such as for example pyridyl-N-oxide.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

The term “heteroarylene” as used herein, alone or in combination, refersto a diradical derived from the above-defined monoradical heteroaryl.Examples include, but are not limited to pyridinyl and pyrimidinyl.

The term “heterocyclyl” as used herein, alone or in combination, referscollectively to heteroalicyclyl and heteroaryl groups. Herein, wheneverthe number of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one non-carbon atom (the heteroatom) must bepresent in the ring. Designations such as “C₁-C₆ heterocycle” refer onlyto the number of carbon atoms in the ring and do not refer to the totalnumber of atoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Forheterocycles having two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Non-aromatic heterocyclic groups includegroups having only three atoms in the ring, while aromatic heterocyclicgroups must have at least five atoms in the ring. Bonding (i.e.attachment to a parent molecule or further substitution) to aheterocycle can be via a heteroatom or a carbon atom.

The term “carbocyclyl” as used herein, alone or in combination, referscollectively to alicyclyl and aryl groups; i.e. all carbon, covalentlyclosed ring structures, which may be saturated, partially unsaturated,fully unsaturated or aromatic. Carbocyclic rings can be formed by three,four, five, six, seven, eight, nine, or more than nine carbon atoms.Carbocycles can be optionally substituted. The term distinguishescarbocyclic from heterocyclic rings in which the ring backbone containsat least one atom which is different from carbon.

The terms “halogen”, “halo” or “halide” as used herein, alone or incombination refer to fluoro, chloro, bromo and iodo.

The term “hydroxy” as used herein, alone or in combination, refers tothe monoradical —OH.

The term “cyano” as used herein, alone or in combination, refers to themonoradical —CN.

The term “cyanomethyl” as used herein, alone or in combination, refersto the monoradical —CH₂CN.

The term “nitro” as used herein, alone or in combination, refers to themonoradical —NO₂.

The term “oxy” as used herein, alone or in combination, refers to thediradical —O—.

The term “oxo” as used herein, alone or in combination, refers to thediradical ═O.

The term “carbonyl” as used herein, alone or in combination, refers tothe diradical —C(═O)—, which may also be written as —C(O)—.

The terms “carboxy” or “carboxyl” as used herein, alone or incombination, refer to the moiety —C(O)OH, which may also be written as—COOH.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, —O-alkyl, including the groups —O-aliphatic and—O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups maybe optionally substituted, and wherein the terms alkyl, aliphatic andcarbocyclyl are as defined herein. Non-limiting examples of alkoxyradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “reactant,” as used herein, refers to a nucleophile orelectrophile used to create covalent linkages.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

Certain Pharmaceutical Terminology

The term “subject”, “patient” or “individual” as used herein inreference to individuals suffering from a disorder, and the like,encompasses mammals and non-mammals. Examples of mammals include, butare not limited to, any member of the Mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, swine; domestic animalssuch as rabbits, dogs, and cats; laboratory animals including rodents,such as rats, mice and guinea pigs, and the like. Examples ofnon-mammals include, but are not limited to, birds, fish and the like.In one embodiment of the methods and compositions provided herein, themammal is a human.

A “disorder associated with HIV infection” or “disease associated withHIV infection” refers to a disease state which is marked by HWinfection. Such disorders associated with HIV infection include, but arenot limited to, AIDS, Kaposi's sarcoma, opportunistic infections such asthose caused by Pneumocystis carinii and Mycobacterium tuberculosis;oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers;generalized lymphadenopathy, shingles, thrombocytopenia, asepticmeningitis, and neurologic disease such as toxoplasmosis,cryptococcosis, CMV infection, primary CNS lymphoma, and HIV-associateddementia, peripheral neuropathies, seizures, and myopathy.

As used herein, a compound that “inhibits replication of humanimmunodeficiency virus (HIV)” means a compound that, when contacted withHIV, for example, via HIV-infected cells, effects a reduction in theamount of HIV as compared with untreated control Inhibition ofreplication of HIV can be measured by various means known in the art,for example, the p24 assay.

The term “Mutant HIV” as used herein refers to a strain of HIV havingone or more mutated or altered amino acids as compared with wild type.

The term “Multi-Drug Resistant HIV” as used herein refers to one or moreHIV strains that are resistant to treatment with one or morechemotherapeutic agents.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition symptoms, preventing additional symptoms,ameliorating or preventing the underlying metabolic causes of symptoms,inhibiting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused bythe disease or condition, or stopping the symptoms of the disease orcondition, and are intended to include prophylaxis. The terms furtherinclude achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in a disease. An appropriate “effective” amount inany individual case may be determined using techniques, such as a doseescalation study.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein, e.g., as discussed in Goodman and Gilman, ThePharmacological Basis of Therapeutics, current ed.; Pergamon; andRemington's, Pharmaceutical Sciences (current edition), Mack PublishingCo., Easton, Pa. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the subject being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compounds described herein, andis relatively nontoxic, i.e., the material may be administered to anindividual without causing undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained.

The term “pharmaceutical composition,” as used herein, refers to abiologically active compound, optionally mixed with at least onepharmaceutically acceptable chemical component, such as, though notlimited to carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “pharmaceutically acceptable derivative or prodrug” as usedherein, refers to any pharmaceutically acceptable salt, ester, salt ofan ester or other derivative of a compound of formula I, which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound of this invention or a pharmaceutically activemetabolite or residue thereof. Particularly favored derivatives orprodrugs are those that increase the bioavailability of the compounds ofthis invention when such compounds are administered to a patient (e.g.,by allowing orally administered compound to be more readily absorbedinto blood) or which enhance delivery of the parent compound to abiological compartment (e.g., the brain or lymphatic system).

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of the specified compound and that are not biologically orotherwise undesirable. Compounds described herein may possess acidic orbasic groups and therefore may react with any of a number of inorganicor organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. These salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound in its freebase form with a suitable organic or inorganic acid, and isolating thesalt thus formed. Examples of pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds described herein witha mineral or organic acid or an inorganic base, such salts including,acetate, acrylate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, bisulfate, bromide, butyrate,butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate,chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate,maleate, malonate, methanesulfonate, mandelate. metaphosphate,methanesulfonate, methoxybenzoate, methylbenzoate,monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate,nicotinate, nitrate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate,phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate,sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate. Other acids, suchas oxalic, while not in themselves pharmaceutically acceptable, may beemployed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts. (See for example Berge et al., J Pharm.Sci. 1977, 66, 1-19.) Further, those compounds described herein whichmay comprise a free acid group may react with a suitable base, such asthe hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation, with ammonia, or with a pharmaceutically acceptableorganic primary, secondary or tertiary amine. Representative alkali oralkaline earth salts include the lithium, sodium, potassium, calcium,magnesium, and aluminum salts and the like. Illustrative examples ofbases include sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and the like. Representative organicamines useful for the formation of base addition salts includeethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,piperazine and the like. It should be understood that the compoundsdescribed herein also include the quaternization of any basicnitrogen-containing groups they may contain. Water or oil-soluble ordispersible products may be obtained by such quaternization. See, forexample, Berge et al., supra.

Pharmaceutically acceptable prodrugs of the compounds described hereininclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters. Variousforms of prodrugs are well known in the art. See for example Design ofProdrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology,Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard,H. “Design and Application of Prodrugs” in A Textbook of Drug Design andDevelopment, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8,1-38, each of which is incorporated herein by reference. The prodrugsdescribed herein include, but are not limited to, the following groupsand combinations of these groups; amine derived prodrugs:

Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfidecontaining esters.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “pharmaceutical combination”, “administering an additionaltherapy”, “administering an additional therapeutic agent” and the like,as used herein, refer to a pharmaceutical therapy resulting from themixing or combining of more than one active ingredient and includes bothfixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that at least one of the compounds describedherein, and at least one co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that at least one of the compoundsdescribed herein, and at least one co-agent, are administered to apatient as separate entities either simultaneously, concurrently orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

The terms “co-administration”, “administered in combination with” andtheir grammatical equivalents or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the compoundsdescribed herein will be co-administered with other agents. These termsencompass administration of two or more agents to an animal so that bothagents and/or their metabolites are present in the animal at the sametime. They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments, the compounds of the invention and the otheragent(s) are administered in a single composition. In some embodiments,compounds of the invention and the other agent(s) are admixed in thecomposition.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

Compounds

Described herein are compounds of formula I:

where the dashed line represents a double bond that may be locatedeither between A and C(V) or between C(V) and D;

A is S or C(Z);

D is S or C(W);

-   -   provided that one and only one of A and D is S;

T is NH, O, or S;

W and Z are, independently, H, F, Cl, Br, C₁-C₆ alkyl; C₂-C₆ alkenyl;OC₁-C₆ alkyl; C₃-C₆ cycloalkyl; OC₃-C₆ cycloalkyl, phenyl, or benzyl,wherein alkyl, alkenyl, cycloalkyl, and phenyl groups and the phenylmoiety of the benzyl group are optionally substituted with 1-3 groupsselected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃ alkyl

V is H, halogen, C₁-C₆ alkyl;

-   -   or V and W, together with the ring atoms to which they are        attached, form an additional, fused 5-, 6-, or 7-membered ring,        optionally containing one or two heteroatoms, which additional        ring may be saturated, unsaturated, or aromatic;    -   or V and Z, together with the ring atoms to which they are        attached, form an additional, fused 5-, 6-, or 7-membered ring,        optionally containing one or two heteroatoms, which additional        ring may be saturated, unsaturated, or aromatic;

Ar is selected from (a), (b), (c), and (d) below:

wherein

-   -   each R^(P) is selected from among methyl, ethyl, propyl,        isopropyl, cyclopropylmethyl, or C₃ C₆ cycloalkyl, cyano,        CH═CHCN, Cl, Br, I, acetyl, and C₁-C₆ alkyl-NH;    -   R⁴, R⁵ and each R⁶ are independently selected from H, F, Cl, Br,        CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,        NH₂, and NHCH₃, or    -   R⁶ and R^(P) on adjacent ring atoms, together with the ring        atoms to which they are attached, form an additional fused        five-membered ring;    -   Q and Q′ are independently selected from N and CH;    -   R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl,        t-butyl, or cyclobutyl; and    -   R⁸-R¹¹ are, independently, H or CH₃;        or a pharmaceutically acceptable salt, solvate, hydrate,        polymorph, ester., tautomer or prodrug thereof.

In one generic embodiment this invention provides a compound of formulaIA, in which the 6-linker T in formula I is T′, which may be O or S.

In one subgeneric embodiment, the invention provides or contemplates acompound of formula IA where Ar is selected from 2-chloro-4-cyclopropylphenyl; 2-methyl-4-cyclopropyl-naphth- 1 -yl;2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl;2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl)phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropylphenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethylphenyl; and 2,6-dimethyl-4-acetyl phenyl.

In another subgeneric embodiment, the invention contemplates a compoundof formula IA where Ar is selected from the following:5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl;5-cyclopropyl-7-trifluoromethyl-8-quinolyl; 5-acetyl-8-quinolyl;5-cyano-7-methoxy-8-quinolyl; 5-cyano-7-methyl-8-quinolyl;5-cyclopropyl-7-trifluoromethoxy-8-isoquinolyl; 5-cyano-8-isoquinolyl;5-cyano-7-methoxy-8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl;5-cyclobutyl-7-difluoromethyl-8-isoquinolyl; 5,7-dimethyl-8-cinnolyl;5-cyclopropyl-7-methyl-8-cinnolyl; and5-(2-cyanoethenyl)-7-methyl-8-cinnolyl.

In another subgeneric embodiment, the invention provides a compound offormula IA-1

where Ar, V, and Z are defined as for formula I.

In another subgeneric embodiment, the invention provides a compound offormula IA-2

where Ar, V, and W are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IA-3

where Ar, V and Z are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IA-4

where Ar, V and W are defined as for formula I.

In another generic embodiment, this invention provides a compound offormula IB

where all substituents are as described above.

In one subgeneric embodiment, the invention provides a compound offormula IB where Ar is (c).

In a more specific subgeneric embodiment, the invention provides acompound of formula IB where Ar is

where RP is CN, CH═CHCN, or cyclopropyl; where R⁶ and R⁷ are either bothmethyl or both methoxy.

In another subgeneric embodiment, this invention provides a compound offormula IB-1.

where Ar, V and W are defined as for formula I.

In another subgeneric embodiment, this invention provides a compound offormula IB-2.

where Ar, V and Z are as described above for formula I.

In more specific embodiments, the invention provides compounds of any ofIA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (a).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (b).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (c).

In additional more specific embodiments, the invention providescompounds of any of IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, where Ar is (d).

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA-1, IA-2, IA-3, or IA-4, whereAr is 2,6-disubstituted-4-cyclopropyl, 2,6-disubstituted-4-acetyl,2,4,6-trimethyl, 2,6-disubstituted-4-bromo, or4-cyano-2,6-di-substituted phenyl.

In a still more specific subgeneric embodiment, this invention providesor contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4, where Aris 4-cyano-2,6-di-methoxy phenyl or 4-cyano-2,6-di-methyl phenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where V is H, halo, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, phenyl, or benzyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-1, IA-2, IA-3, orIA-4, where A is S and W is H, C₃-C₆ cycloalkyl, or OC₃-C₆ cycloalkyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, unsubstituted C₁-C₄ alkyl, monosubstitutedC₁-C₄ alkyl, or C₂-C₃ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and W is H, halo, halomethyl, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and V and W, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered carbocyclicring.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where A is S and V and W, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered ring, whichring contains one or two heteroatoms selected from O, N, and S.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, C₁-C₆ alkyl, or C₂-C₆ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, C₃-C₆ cycloalkyl, or OC₃-C₆ cycloalkyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, unsubstituted C₁-C₄ alkyl, monosubstitutedC₁-C₄ alkyl, or C₂-C₃ alkenyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and Z is H, halo, halomethyl, or methyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates a compound of formula IA-1, IA-2, IA-3, orIA-4, where D is S and Z is H, phenyl, or benzyl.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and V and Z, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered carbocyclicring.

In another still more specific subgeneric embodiment, this inventionprovides or contemplates compounds of formula IA-1, IA-2, IA-3, or IA-4,where D is S and V and Z, together with the ring atoms to which they areattached, form an additional, fused 5-, 6-, or 7-membered ring, whichring contains one or two heteroatoms selected from O, N, and S.

Synthetic Procedures

In another aspect, methods for synthesizing the compounds describedherein are provided. In some embodiments, the compounds described hereincan be prepared by the methods described below. The procedures andexamples below are intended to illustrate those methods. Neither theprocedures nor the examples should be construed as limiting theinvention in any way. Compounds described herein may also be synthesizedusing standard synthetic techniques known to those of skill in the artor using methods known in the art in combination with methods describedherein. In additions, solvents, temperatures and other reactionconditions presented herein may vary according to the practice andknowledge of those of skill in the art.

The starting materials used for the synthesis of the compounds asdescribed herein can be obtained from commercial sources, such asAldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis,Mo.), or the starting materials can be synthesized. The compoundsdescribed herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001), and Green and WITS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999) (all of which are incorporated by reference in theirentirety). General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods may be utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. The table below entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

Examples of Covalent Linkages and Precursors Thereof Covalent LinkageProduct Electrophile Nucleophile Carboxamides Activated estersAmines/anilines Carboxamides Acyl azides Amines/anilines CarboxamidesAcyl halides Amines/anilines Esters Acyl halides Alcohols/phenols EstersAcyl nitriles Alcohols/phenols Carboxamides Acyl nitrilesAmines/anilines Imines Aldehydes Amines/anilines Hydrazones Aldehydes orketones Hydrazines Oximes Aldehydes or ketones Hydroxylamines Alkylamines Alkyl halides Amines/anilines Esters Alkyl halides Carboxylicacids Thioethers Alkyl halides Thiols Ethers Alkyl halidesAlcohols/phenols Thioethers Alkyl sulfonates Thiols Esters Alkylsulfonates Carboxylic acids Ethers Alkyl sulfonates Alcohols/phenolsEsters Anhydrides Alcohols/phenols Carboxamides AnhydridesAmines/anilines Thiophenols Aryl halides Thiols Aryl amines Aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides Carboxylic acids Amines/anilines Esters Carboxylic acidsAlcohols Hydrazines Hydrazides Carboxylic acids N-acylureas orAnhydrides Carbodiimides Carboxylic acids Esters Diazoalkanes Carboxylicacids Thioethers Epoxides Thiols Thioethers Haloacetamides ThiolsAmmotriazines Halotriazines Amines/anilines Triazinyl ethersHalotriazines Alcohols/phenols Amidines Imido esters Amines/anilinesUreas Isocyanates Amines/anilines Urethanes Isocyanates Alcohols/phenolsThioureas Isothiocyanates Amines/anilines Thioethers Maleimides ThiolsPhosphite esters Phosphoramidites Alcohols Silyl ethers Silyl halidesAlcohols Alkyl amines Sulfonate esters Amines/anilines ThioethersSulfonate esters Thiols Esters Sulfonate esters Carboxylic acids EthersSulfonate esters Alcohols Sulfonamides Sulfonyl halides Amines/anilinesSulfonate esters Sulfonyl halides Phenols/alcoholsUse of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Protecting groups are used toblock some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. Protective groups can be removed by acid, base, andhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Protecting or blocking groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference in their entirety.

Preparing Compounds of formula I

Compounds of this invention are prepared according to the syntheticroutes presented in schemes 1-3 and following typical syntheticprocedures. Where appropriate, standard blocking or protecting methodswell-known in the art of synthetic organic chemistry may be required.Such circumstances will be readily recognized by persons of skill in theart.

Further Forms of Compounds of formula IIsomers of Compounds of Formula I

The compounds described herein may exist as geometric isomers. Thecompounds described herein may possess one or more double bonds. Thecompounds presented herein include all cis, trans, syn, anti, entgegen(E), and zusammen (Z) isomers as well as the corresponding mixturesthereof. In some situations, compounds may exist as tautomers. Thecompounds described herein include all possible tautomers within theformulas described herein. The compounds described herein may possessone or more chiral centers and each center may exist in the R or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion may also be useful for the applications describedherein. The compounds described herein can be prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of the compoundsdescribed herein, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.

Labeled Compounds of Formula I

Also described herein are isotopically-labeled compounds of formula Iand methods of treating disorders. For example, the invention providesfor methods of treating diseases, by administering isotopically-labeledcompounds of formula I. The isotopically-labeled compounds of formula Ican be administered as pharmaceutical compositions. Thus, compounds offormula I also include isotopically-labeled compounds, which areidentical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸0, ¹⁷O, ³¹P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compoundsdescribed herein, pharmaceutically acceptable salts, esters, prodrugs,solvate, hydrates or derivatives thereof which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labeled compounds offormula I, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i. e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds,pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof can generally be prepared by carrying out proceduresdescribed herein, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

The compounds described herein may be labeled by other means, including,but not limited to, the use of chromophores or fluorescent moieties,bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts of Compounds of Formula I

Also described herein are pharmaceutically acceptable salts of compoundsof formula I and methods of treating disorders. For example, theinvention provides for methods of treating diseases, by administeringpharmaceutically acceptable salts of compounds of formula I. Thepharmaceutically acceptable salts of compounds of formula I can beadministered as pharmaceutical compositions.

Thus, the compounds described herein can be prepared as pharmaceuticallyacceptable salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, for example an alkali metalion, an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base. Base addition salts can also be prepared by reacting thefree acid form of the compounds described herein with a pharmaceuticallyacceptable inorganic or organic base, including, but not limited toorganic bases such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like and inorganic bases suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like. In addition, the salt formsof the disclosed compounds can be prepared using salts of the startingmaterials or intermediates.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1 -carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

Solvates of Compounds of Formula I

Also described herein are solvates of compounds of formula I and methodsof treating disorders. For example, the invention provides for methodsof treating diseases, by administering solvates of compounds of formulaI. The solvates of compounds of formula I can be administered aspharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and may be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of the compounds describedherein can be conveniently prepared or formed during the processesdescribed herein. By way of example only, hydrates of the compoundsdescribed herein can be conveniently prepared by recrystallization froman aqueous/organic solvent mixture, using organic solvents including,but not limited to, dioxane, tetrahydrofuran or methanol. In addition,the compounds provided herein can exist in unsolvated as well assolvated forms. In general, the solvated forms are considered equivalentto the unsolvated forms for the purposes of the compounds and methodsprovided herein.

Polymorphs of Compounds of Formula I

Also described herein are polymorphs of compounds of formula I andmethods of treating disorders. For example, the invention provides formethods of treating diseases, by administering polymorphs of compoundsof formula I. The polymorphs of compounds of formula I can beadministered as pharmaceutical compositions.

Thus, the compounds described herein include all their crystallineforms, known as polymorphs. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs may have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and solubility. Various factors suchas the recrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

Prodrugs of Compounds of Formula I

Also described herein are prodrugs of compounds of formula I and methodsof treating disorders. For example, the invention provides for methodsof treating diseases, by administering prodrugs of compounds of formulaI. The prodrugs of compounds of formula I can be administered aspharmaceutical compositions.

Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they may be easier to administer than theparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound asdescribed herein which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyamino acid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety.

Prodrugs may be designed as reversible drug derivatives, for use asmodifiers to enhance drug transport to site-specific tissues. The designof prodrugs to date has been to increase the effective water solubilityof the therapeutic compound for targeting to regions where water is theprincipal solvent. See, e.g., Fedorak et al., Am. J. Physiol.,269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994);Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H.Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int.J Pharmaceutics, 47, 103 (1988); Sinkula et al., J Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein in theirentirety.

Additionally, prodrug derivatives of compounds described herein can beprepared by methods known to those of ordinary skill in the art (e.g.,for further details see Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985). By way of example only,appropriate prodrugs can be prepared by reacting a non-derivatizedcompound of formula I with a suitable carbamylating agent, such as, butnot limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenylcarbonate, or the like. Prodrug forms of the herein described compounds,wherein the prodrug is metabolized in vivo to produce a derivative asset forth herein are included within the scope of the claims. Indeed,some of the herein-described compounds may be a prodrug for anotherderivative or active compound.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e. g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids commonly designated bythree letter symbols and also includes 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone. Additional types of prodrugs are alsoencompassed.

Compounds of formula I having free amino, amido, hydroxy or carboxylicgroups can be converted into prodrugs. For instance, free carboxylgroups can be derivatized as amides or alkyl esters. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups.

Derivatization of hydroxy groups as (acyloxy) methyl and (acyloxy) ethylethers wherein the acyl group may be an alkyl ester, optionallysubstituted with groups including but not limited to ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem. 1996, 39, 10. Free amines can alsobe derivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities.

Sites on the aromatic ring portions of compounds of formula I may besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, can reduce,minimize or eliminate this metabolic pathway.

Methods

The present invention also provides methods for treating or amelioratingHW disease and related diseases. The method includes administering atherapeutically effective dosage of at least one compound of theinvention to a subject suffering from HIV disease or HIV-relateddiseases. The invention also provides a method of combination therapy inwhich one or more compound of the invention is administered incombination with one or more other compound having activity against HWdisease or HIV-related disease.

Furthermore, the invention provides methods for inhibiting drugresistant HW mutants. The high replication rate of HIV leads to geneticvariants (mutants), especially when selective pressure is introduced inthe form of drug treatment. The mutants frequently display resistance toanti-viral agents previously administered to the patient. Switchingagents or using combination therapies may decrease or delay resistance,but because viral replication is not completely suppressed in singledrug treatment or even with a two-drug combination, drug-resistant viralstrains ultimately emerge. Triple drug combinations employing one (ortwo) nucleoside analogs and two (or one) non-nucleoside inhibitor (NNI)targeting RT provide a very promising therapy to overcome the drugresistance problem. RT mutant strains resistant to such a triple actiondrug combination would most likely not be able to function. Many mutantstrains have been characterized as resistant to NNI compounds, includingL1001, K103N, V106A, E 138K, Y181C and Y188H. In particular, the Y181Cand K103N mutants may be the most difficult to treat, because they areresistant to most of the NNI compounds that have been examined.

Pharmaceutical Compositions

Described herein are pharmaceutical compositions. In some embodiments,the pharmaceutical compositions comprise an effective amount of acompound formula I, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof. In some embodiments,the pharmaceutical compositions comprise an effective amount of acompound formula I, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof and at least onepharmaceutically acceptable carrier. In some embodiments thepharmaceutical compositions are for the treatment of disorders. In someembodiments the pharmaceutical compositions are for the treatment ofdisorders in a mammal. In some embodiments the pharmaceuticalcompositions are for the treatment of disorders in a human. In someembodiments the pharmaceutical compositions are for the treatment ofHIV/AIDS.

Modes of Administration

Described herein are compounds of formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.Also described, are pharmaceutical compositions comprising a compound offormula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof. The compounds and compositionsdescribed herein may be administered either alone or in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition, according to standard pharmaceuticalpractice.

Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include oral routes, intraduodenal routes,parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical, andrectal administration. For example, compounds described herein can beadministered locally to the area in need of treatment. This may beachieved by, for example, but not limited to, local infusion duringsurgery, topical application, e.g., cream, ointment, injection,catheter, or implant, said implant made, e.g., out of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. The administration can also be by directinjection at the site (or former site) of a tumor or neoplastic orpre-neoplastic tissue. Those of ordinary skill in the art are familiarwith formulation and administration techniques that can be employed withthe compounds and methods of the invention, e.g., as discussed inGoodman and Gilman, The Pharmacological Basis of Therapeutics, currented.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. All methodsinclude the step of bringing into association a compound of the subjectinvention or a pharmaceutically acceptable salt, ester, prodrug orsolvate thereof (“active ingredient”) with the carrier which constitutesone or more accessory ingredients. In general, the formulations areprepared by uniformly and intimately bringing into association theactive ingredient with liquid carriers or finely divided solid carriersor both and then, if necessary, shaping the product into the desiredformulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Pharmaceutical preparations may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical preparations may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical preparations may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical preparations suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation. It may however comprise as much as 10% w/wbut preferably will comprise less than 5% w/w, more preferably from 0.1%to 1% w/w of the formulation.

Pharmaceutical preparations for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Formulations

The compounds or compositions described herein can be delivered in avesicle, e.g., a liposome (see, for example, Langer, Science 1990,249,1527-1533; Treat et al., Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp.353-365, 1989).The compounds and pharmaceutical compositions describedherein can also be delivered in a controlled release system. In oneembodiment, a pump may be used (see, Sefton, 1987, CRC Crit. Ref.Biomed. Eng. 14:201; Buchwald et al. Surgery, 1980 88, 507; Saudek etal. N Engl. J. Med. 1989, 321, (574). Additionally, a controlled releasesystem can be placed in proximity of the therapeutic target. (See,Goodson, Medical Applications of Controlled Release, 1984, Vol. 2, pp.115-138). The pharmaceutical compositions described herein can alsocontain the active ingredient in a form suitable for oral use, forexample, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules, orsyrups or elixirs. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium crosscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of an oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor arachis oil, or a mineral oil, for example liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous solution. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. The sterile injectable preparation may also be a sterileinjectable oil-in-water microemulsion where the active ingredient isdissolved in the oily phase. For example, the active ingredient may befirst dissolved in a mixture of soybean oil and lecithin. The oilsolution then introduced into a water and glycerol mixture and processedto form a microemulsion. The injectable solutions or microemulsions maybe introduced into a patient's blood-stream by local bolus injection.Alternatively, it may be advantageous to administer the solution ormicroemulsion in such a way as to maintain a constant circulatingconcentration of the instant compound. In order to maintain such aconstant concentration, a continuous intravenous delivery device may beutilized. An example of such a device is the Deltec CADD-PLUSTM model5400 intravenous pump. The pharmaceutical compositions may be in theform of a sterile injectable aqueous or oleagenous suspension forintramuscular and subcutaneous administration. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the inhibitors with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a compound or composition of the invention can be used.As used herein, topical application can include mouth washes andgargles.

Pharmaceutical compositions may be administered in intranasal form viatopical use of suitable intranasal vehicles and delivery devices, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

Doses

The amount of pharmaceutical compositions administered will firstly bedependent on the mammal being treated. In the instances wherepharmaceutical compositions are administered to a human subject, thedaily dosage will normally be determined by the prescribing physicianwith the dosage generally varying according to the age, sex, diet,weight, general health and response of the individual patient, theseverity of the patient's symptoms, the precise indication or conditionbeing treated, the severity of the indication or condition beingtreated, time of administration, route of administration, thedisposition of the composition, rate of excretion, drug combination, andthe discretion of the prescribing physician. Also, the route ofadministration may vary depending on the condition and its severity.Preferably, the pharmaceutical composition is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small amounts until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. Theamount and frequency of administration of the compounds describedherein, and if applicable other therapeutic agents and/or therapies,will be regulated according to the judgment of the attending clinician(physician) considering such factors as described above. Thus the amountof pharmaceutical composition to be administered may vary widely.Administration may occur in an amount of between about 0.001 mg/kg ofbody weight to about 100 mg/kg of body weight per day (administered insingle or divided doses), more preferably at least about 0.1 mg/kg ofbody weight per day. A particular therapeutic dosage can include, e.g.,from about 0.01 mg to about 7000 mg of compound, and preferablyincludes, e.g., from about 0.05 mg to about 2500 mg. The quantity ofactive compound in a unit dose of preparation may be varied or adjustedfrom about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, morepreferably 10 mg to 200 mg, according to the particular application. Insome instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesmay be employed without causing any harmful side effect, e.g. bydividing such larger doses into several small doses for administrationthroughout the day. The amount administered will vary depending on theparticular IC₅₀ value of the compound used. In combinationalapplications in which the compound is not the sole therapy, it may bepossible to administer lesser amounts of compound and still havetherapeutic or prophylactic effect.

Dosage Forms

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 18th Edition (1990).

Combination Therapies

The compounds described herein or a pharmaceutically acceptable salt,solvate, polymorph, ester, tautomer or prodrug thereof may beadministered as a sole therapy. The compounds described herein or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof may also be administered in combination with anothertherapy or therapies.

By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds described herein ishypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the compound. Or, by way ofexample only, the therapeutic effectiveness of one of the compoundsdescribed herein may be enhanced by administration of an adjuvant (i.e.,by itself the adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit experienced by a patient may be increased by administering oneof the compounds described herein with another therapeutic agent (whichalso includes a therapeutic regimen) that also has therapeutic benefit.By way of example only, in a treatment for HIV/AIDS involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for HIV/AIDS. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Other therapies include, but are not limited to administration of othertherapeutic agents. In the instances where the compounds describedherein are administered with other therapeutic agents, the compoundsdescribed herein need not be administered in the same pharmaceuticalcomposition as other therapeutic agents, and may, because of differentphysical and chemical characteristics, be administered by a differentroute. For example, the compounds/compositions may be administeredorally to generate and maintain sufficient blood levels thereof, whilethe other therapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician. The particular choice of compound will depend uponthe diagnosis of the attending physicians and their judgment of thecondition of the patient and the appropriate treatment protocol.

The present invention provides methods for treating or ameliorating HIVdisease and related diseases. The method includes administering atherapeutically effective dosage of at least one compound of theinvention to a subject suffering from HIV disease or HIV-relateddiseases. The invention also provides a method of combination therapy inwhich one or more compound of the invention is administered incombination with one or more other compound having activity against HIVdisease or HIV-related disease.

Kits

The compounds, compositions and methods described herein provide kitsfor the treatment of disorders, such as the ones described herein. Thesekits comprise a compound, compounds or compositions described herein ina container and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in some embodiments,be marketed directly to the consumer.

The compounds described herein can be utilized for diagnostics and asresearch reagents. For example, the compounds described herein, eitheralone or in combination with other compounds, can be used as tools indifferential and/or combinatorial analyses to elucidate expressionpatterns of genes expressed within cells and tissues. As onenon-limiting example, expression patterns within cells or tissuestreated with one or more compounds are compared to control cells ortissues not treated with compounds and the patterns produced areanalyzed for differential levels of gene expression as they pertain, forexample, to disease association, signaling pathway, cellularlocalization, expression level, size, structure or function of the genesexamined. These analyses can be performed on stimulated or unstimulatedcells and in the presence or absence of other compounds which affectexpression patterns.

Besides being useful for human treatment, the compounds and formulationsof the present invention are also useful for veterinary treatment ofcompanion animals, exotic animals and farm animals, including mammals,rodents, and the like. More preferred animals include horses, dogs, andcats.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES

I. Chemical Syntheses

Commercially available methyl-2-aminothiophene-3-carboxylate wascyclized to thieno[2,3]pyrimidine by first treating with potassiumcyanate followed by refluxing in 6% aqueous sodium hydroxide solution.Chlorination with phosphonyl chloride provided the dichlorothienopyrimidine. R²H (defined as a substituted or unsubstitutedaniline, a substituted or unsubstituted phenol or a substituted orunsubstituted thiophenol) was coupled on the ring system withtrifluoroethanol and trifluoroacetic acid (when R²H is a substituted orunsubstituted aniline), sodium hydride (when R²H is a substituted orunsubstituted phenol), or DBU (when R²H is a substituted orunsubstituted thiophenol). 4-Amino benzonitrile was coupled in thepresence of trifluoroethanol and trifluoroacetic acid to provide aseries of thieno[2,3-d]pyrimidine compounds with various R²substitutions.

Example 1 Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a stirred solution of methyl-2-aminothiophene-3-carboxylate (2.03 g,12.9 mmol) in acetic acid (65 mL) and water (6.5 mL) was added asolution of potassium cyanate (3.14 g, 38.7 mmol) dissolved in water(10.4 mL) dropwise via syringe. The reaction was stirred at roomtemperature for 15 h, upon completion of the reaction; the reactionmixture was concentrated to 75% and filtered off white solid. To thesolid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2h. After cooling to room temperature, the solution was acidified using12N HC1 to pH=6. The resultant precipitate was filtered, washed withwater and dried in a vacuum oven overnight to give 546 mg (25%) of thetitle compound as an orange solid which was used without any furtherpurification:

¹H NMR (DMSO, 300 MHz) δ 7.06 (d, J=5.7 Hz, 1H), 7.1 (d, J=5.7 Hz, 1H),11.1 (broad s, 1H), 11.9 (broad s, 1H).

Example 2 2,4-Dichlorothieno[2,3-d]pyrimidine

A mixture of thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.59mmol) and phosphonyl chloride (2 mL, 21.5 mmol) was heated at 116° C.for 3 h. Upon completion of the reaction, the reaction mixture waspoured into ice and extract with ethyl acetate 3 times. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by column chromatography, elutingwith Hexanes/Ethyl Acetate (9:1) afforded the product as a white solid(48.1 mg, 40%):

¹H NMR (DMSO, 300 MHz) δ 7.6 (d, J=6.3 Hz, 1H), 8.13(d, J=5.7 Hz, 1H).

Example 3 2-Chloro-4-(mesityloxy)thieno[2,3-d]pyrimidine

A stirred suspension of NaH (9.5 mg, 0.24 mmol) in dry THF (1 mL) wasadded 2,4,6-trimethyl phenol (32.1 mg, 0.24 mmol) and stirred at roomtemperature for 30 min under Argon. The reaction mixture was added to asolution of 2,4-dichlorothieno[2,3-d]pyrimidine (48.1 mg, 0.24 mmol) indry THF (1.5 mL) at 0° C. and allow it to slowly warmed up to roomtemperature. After stirring the reaction for 4 h, the resulting mixturewas diluted with water and washed with EtOAc. The combined organiclayers were washed with water, brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography, eluting with hexanes/ethyl acetate (9:1) to give theproduct as a white solid (71 mg, 97%):

¹H NMR (DMSO, 300 MHz) δ 2.0 (s, 6H), 2.27 (s, 3H), 6.98 (s, 2H), 7.65(d, J=6.0 Hz, 1H), 7.75 (d, J=5.7 Hz, 1H).

Example 4 4-(4-Mesityloxy)thieno[2,3-d]pyrimidin-2-ylamino)benzonitrile

To a solution of 2-chloro-4-(mesityloxy)thieno[2,3-d]pyrimidine (71 mg,0.23 mmol), TFA (0.15 mL, 1.84 mmol) in TFE (1.3 mL) was added4-aminobenzonitrile (110 mg, 0.93 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate (5 mL) and washed with saturated NaHCO₃ (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep plateeluting with Hexanes/ethyl acetate (3:1) give product as white solid (29mg, 33%):

¹H NMR (DMSO, 300 MHz) δ 2.0 (s, 6H), 2.31 (s, 3H), 7.02 (s, 2H), 7.46(d, J=8.1 Hz, 2H), 7.51 (d, J=6.3 Hz, 1H), 7.55 (d, J=5.4 Hz, 1H), 7.62(d, J=9.0 Hz, 2H), 10.15 (s, 1H).

Example 54-(2-Chlorothieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile

A stirred suspension of NaH (85 mg, 2.12 mmol) in dry THF (12 mL) wasadded 4-hydroxy-3,5-dimethyl benzonitrile (311 mg, 2.12 mmol) andstirred at room temperature for 30 min under Argon. The reaction mixturewas added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (434 mg,2.12 mmol) in dry THF (10 mL) and heated at 50° C. for 2 h, theresulting mixture was diluted with water and washed with EtOAc. Thecombined organic layers were washed with water, brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography, eluting with hexanes/ethyl acetate(5:1) to give the product as a white solid (188 mg, 28%):

¹H NMR (DMSO, 300 MHz) 6 2.10 (s, 6H), 7.72 (d, J=5.7 Hz, 1H), 7.75 (s,2H), 8.02 (d, J=6.0 Hz, 1H).

Example 64-(2-(4-Cyanophenylamino)thieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile

To a solution of4-(2-chlorothieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (188mg, 0.59 mmol), TFA (0.37 mL, 4.75 mmol) in TFE (2.5 mL) was added4-aminobenzonitrile (280 mg, 2.37 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 2 d. Reaction mixture was diluted with ethylacetate (5 mL) and washed with saturated NaHCO₃ (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by HPLC affordedthe product as white solid (34 mg, 14%):

¹H NMR (DMSO, 300 MHz) δ 2.12 (s, 6H), 7.60-7.50 (m, 6H), 10.12 (s, 1H).

Example 7 2-Chloro-N-mesitylthieno[2,3-d]pyrimidin-4-amine

To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (805 mg, 3.94mmol), TFA (0.91 mL, 11.82 mmol) in TFE (11 mL) was added2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. Thereaction was stirred at 90° C. for 2 d. Reaction mixture was dilutedwith CH₂Cl₂ and washed with saturated NaHCO₃ (3×20 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by HPLC to affordthe product as a white solid (43.4 mg, 36%):

¹H NMR (DMSO, 300 MHz) δ 2.08 (s, 6H), 2.27 (s, 3H), 6.97 (s, 2H), 7.69(d, J=6.0 Hz, 1H), 7.78 (d, J=6.0 Hz, 1H), 9.68 (s, 1H).

Example 8 4-(4-Mesitylamino)thieno[2,3-d]pyrimidin-2-ylamino)benzonitrile

To a solution of 2-Chloro-N-mesitylthieno[2,3-d]pyrimidin-4-amine (43.4mg, 0.14 mmol), TFA (0.09 mL, 1.14 mmol) in TFE (0.6 mL) was added4-aminobenzonitrile (68 mg, 0.57 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate and washed with saturated NaHCO₃ (3×10 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep plate withHexanes/ethyl acetate (2:1) as eluant to afford the product as a whitesolid (55.1 mg, 8%):

¹H NMR (DMSO, 300 MHz) δ 2.11 (s, 6H), 2.32 (s, 3H), 6.12 (s, 2H), 6.58(d, J=8.4 Hz, 2H), 7.02 (d, J=6.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.66(d, J=6.0 Hz, 1H), 9.27 (s, 1H), 9.68 (s, 1H).

Chlorination of commercially availablethieno[3,2-d]pyrimidine-2,4(1H,3H)-dione with phosphonyl chlorideprovided the dichloro-thienopyrimidine. R²H (defined as a substituted orunsubstituted aniline, a substituted or unsubstituted phenol or asubstituted or unsubstituted thiophenol) was coupled on the ring systemwith trifluoroethanol and trifluoroacetic acid (when R²H is asubstituted or unsubstituted aniline), sodium hydride (when R²H is asubstituted or unsubstituted phenol), or DBU (when R²H is a substitutedor unsubstituted thiophenol). 4-Aminobenzonitrile was coupled in thepresence of trifluoroethanol and trifluoroacetic acid to provide aseries of thieno[3,2-d]pyrimidine derivatives with various R²substitutions.

Example 9 2,4-Diehlorothieno[3,2-d]pyrimidine

A mixture of thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (1.02 g, 6.07mmol) and phosphonyl chloride (15 mL, 161 mmol) was heated at 116° C.for 5 h. Upon completion of the reaction, the reaction mixture waspoured into ice and extract with ethyl acetate 3 times. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by column chromatography, elutingwith Hexanes/Ethyl Acetate (9:1) afforded the product as a white solid(343 mg, 28%):

¹H NMR (DMSO, 300 MHz) δ 7.73 (d, J=5.4 Hz, 1H), 8.69 (d, J=5.7 Hz, 1H).

Example 10 2-Chloro-4-(mesityloxy)thieno[3,2-d]pyrimidine

A stirred suspension of NaH (7.8 mg, 0.19 mmol) in dry THF (1 mL) wasadded 2,4,6-trimethyl phenol (26.4 mg, 0.19 mmol) and stirred at roomtemperature for 30 min under Argon. The reaction mixture was added to asolution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) indry THF (1 mL) at 0° C. and allow it to slowly warmed up to roomtemperature. After stirring the reaction for 4 h, the resulting mixturewas diluted with water and washed with EtOAc. The combined organiclayers were washed with water, brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography, eluting with hexanes/ethyl acetate (9:1) to give theproduct as a white solid (32.4 mg, 56%):

¹H NMR (DMSO, 300 MHz) δ 2.0 (s, 6H), 2.27 (s, 3H), 6.98 (s, 2H), 7.68(d, J=6.0 Hz, 1H), 7.97 (d, J=5.7 Hz, 1H).

Example 114-(4-(mesityloxy)thieno[3,2-d]pyrimidin-2-ylamino)benzonitrile

To a solution of 2-chloro-4-(mesityloxy)thieno[3,2-d]pyrimidine (32.4mg, 0.11 mmol), TFA (0.13 mL, 1.71 mmol) in TFE (0.7 mL) was added4-aminobenzonitrile (100 mg, 0.88 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate (5 mL) and washed with saturated NaHCO₃ (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep HPLCafforded the product as a white solid (26.7 mg, 63%):

¹H NMR (DMSO, 300 MHz) δ 2.05 (s, 6H), 2.27 (s, 3H), 7.02 (s, 2H), 7.37(d, J=5.7 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 8.27(d, J=5.7 Hz, 1H), 10.05 (s, 1H).

Example 12 4-(2-Chlorothieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile

A stirred suspension of NaH (29.7 mg, 0.74 mmol) in dry NMP (3.5 mL) wasadded 4-hydroxy-3,5-dimethylbenzonitrile (108.2 mg, 0.74 mmol) andstirred at room temperature for 30 min under Argon. The reaction mixturewas added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg,0.19 mmol) in dry NMP (4 mL) and heated at 50° C. for 5 h. The resultingmixture was diluted with water and washed with EtOAc. The combinedorganic layers were washed with water, brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography, eluting with hexanes/ethyl acetate (4:1) to givethe product as a white solid (189 mg, 81%):

¹H NMR (DMSO, 300 MHz) δ 2.11 (s, 6H), 7.68 (d, J=5.7 Hz, 1H), 7.76 (s,2H), 8.59 (d, J=5.4 Hz, 1H).

Example 134-(2-(4-cyanophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile

To a solution of4-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (187mg, 0.6 mmol), TFA (0.37 mL, 4.8 mmol) in TFE (3 mL) was added4-aminobenzonitrile (283 mg, 2.4 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate (5 mL) and washed with saturated NaHCO₃ (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep HPLCafforded the product as a white solid (81 mg, 34%):

¹H NMR (DMSO, 300 MHz) δ 2.16 (s, 6H), 7.47 (d, J=5.4 Hz, 1H), 7.53 (d,J=8.7 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.80 (s, 2H), 8.40 (d, J=5.4 Hz,1H), 10.06 (s, 1H).

Example 14 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine

To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (148 mg, 0.73mmol), TFA (0.17 mL, 2.19 mmol) in TFE (2 mL) was added2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. Thereaction was stirred at 90° C. for 15 h. The reaction mixture wasdiluted with CH₂Cl₂ and washed with saturated NaHCO₃ solution (3×20 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bycolumn chromatography eluting with Hexanes:ethyl acetate (4:1) to affordthe product as a white solid (51.4 mg, 23%):

¹H NMR (DMSO, 300 MHz) δ 2.17 (s, 6H), 2.37 (s, 3H), 6.76, (d, J=5.7 Hz,1H), 6.94 (broad s, 1H), 6.99 (s, 2H), 7.6 (d,J=5.7 Hz, 1H).

Example 154-(4-(mesitylamino)thieno[3,2-d]pyrimidin-2-ylamino)benzonitrile

To a solution of 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine (51.4mg, 0.17 mmol), TFA (0.11 mL, 1.36 mmol) in TFE (1 mL) was added4-aminobenzonitrile (80.2 mg, 0.68 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate and washed with saturated NaHCO₃ (3×10 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep HPLC toafford the product as a white solid (13 mg, 20%): ¹H NMR (DMSO, 300 MHz)δ 2.09 (s, 6H), 2.31 (s, 3H), 7.00 (s, 2H), 7.28 (d, J=5.7 Hz, 1H), 7.66(d, J=8.4 Hz, 2H), 8.06-8.08 (m, 3H), 9.60 (bs, 1H), 9.72 (bs, 1H).

Starting with commercially availablemethyl-3-amino-4-methylthiophene-2-carboxylate and cyclized tothieno[3,2]pyrimidine by first treating with potassium cyanate followedby refluxing in 6% aqueous sodium hydroxide solution. Chlorination withphosphonyl chloride provided the dichloro-thienopyrimidine. R²H (definedas above) was coupled on the ring system with trifluoroethanol andtrifluoroacetic acid (when R²H is a substituted or unsubstitutedaniline), sodium hydride (when R²H is a substituted or unsubstitutedphenol), or DBU (when R²H is a substituted or unsubstituted thiophenol).4-Aminobenzonitrile was coupled in the presence of trifluoroethanol andtrifluoroacetic acid to provide a series of7-methylthieno[3,2-d]pyrimidine compounds with various R² substitutions.

Example 16 7-Methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

To a stirred solution of methyl-3-amino-4-methylthiophene-2-carboxylate(530 mg, 3.1 mmol) in acetic acid (15.5 mL) and water (1.6 mL) was addeda solution of potassium cyanate (754 mg, 9.3 mmol) dissolved in water(2.5 mL) dropwise via syringe. The reaction was stirred at roomtemperature for 15 h, upon completion of the reaction; the reactionmixture was concentrated to 75% and filtered off white solid. To thesolid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2h. After cooling to room temperature, the solution was acidified using12N HCl to pH=6. The resultant precipitate was filtered, washed withwater and dried in vacuum oven overnight to give 403 mg (71%) of thetitle compound as a white solid which was used without any furtherpurification:

¹H NMR (DMSO, 300 MHz) δ 2.17 (s, 3H), 7.67 (s, 1H), 11.21 (bs, 1H),11.4 (bs, 1H).

Example 17 2,4-Dichloro-7-methylthieno [3,2-d]pyrimidine

A mixture of 7-methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (403 mg,2.21 mmol) and phosphonyl chloride (8.0 mL, 86 mmol) was heated at 116°C. for 4 h. Upon completion of the reaction, the reaction mixture waspoured onto ice and extracted with ethyl acetate 3 times. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by column chromatography, elutingwith Hexanes/Ethyl Acetate (5:1) afforded the product as a white solid(145 mg, 88%):

¹H NMR (DMSO, 300 MHz) δ 2.39 (s, 3H), 8.34 (s, 1H).

Example 18 2-Chloro-4-(mesityloxy)-7-methylthieno [3,2-d]pyrimidine

A stirred suspension of NaH (16 mg, 0.4 mmol) in dry THF (2 mL) wasadded 2,4,6-trimethyl phenol and stirred at room temperature for 30 minunder argon. The reaction mixture was added to a solution of2,4-ichloro-7-methylthieno[3,2-d]pyrimidine (87 mg, 0.4 mmol) in dry THF(2 mL) at 0° C. and slowly warmed up to room temperature. After stirringthe reaction for 2 h, the resulting mixture was diluted with water andwashed with EtOAc. The combined organic layers were washed with water,brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography, eluting withhexanes/ethyl acetate (2:1) to give the product as a white solid (136mg, 90%):

¹H NMR (DMSO, 300 MHz) δ 2.0 (s, 3H), 2.08 (s, 6H), 2.37 (s, 3H), 6.99(s, 2H), 7.87 (s, 1H).

Example 194-(4-Mesityloxy)-7-methylthieno[3,2-d]pyrimidin-2-ylamino)benzonitrile

To a solution of 2-chloro-4-(mesityloxy)-7-methylthieno[3,2-d]pyrimidine(136 mg, 0.43 mmol), TFA (0.26 mL, 3.42 mmol) in TFE (1.43 mL) was added4-aminobenzonitrile (202 mg, 1.71 mmol) in a sealed tube. The reactionwas stirred at 90° C. for 15 h. Reaction mixture was diluted with ethylacetate (5 mL) and washed with saturated NaHCO₃ (3×10 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by prep plate,eluting with hexanes/ethyl acetate (2:1) to give the product as a whitesolid (7.6 mg, 5.3%):

¹H NMR (DMSO, 300 MHz) δ 2.0s (s, 6H), 2.31 (s, 3H), 2.37 (s, 3H), 7.02(s, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.98 (s, 1H),10.06 (s, 1H).

II. Biological Activity

Example 20 Inhibition of HIV-1 Reverse Transcriptase

Numerous compounds were screened for inhibitory activity against humanimmunodeficiency virus type 1 (HIV-1) using a high throughput cell-basedassay using HIV-1 expressing firefly luciferase as a reporter gene andpseudotyped with vesicular stomatitis virus envelope glycoprotein(VSV-G). Experimental procedures were essentially as described by Connoret al. in Journal of Virology (1996), 70: 5306-5311 (Characterization ofthe functional properties of env genes from long-term survivors of humanimmunodeficiency virus type 1 infection), and Popik et al. in Journal ofVirology (2002), 76: 4709-4722 (Human immunodeficiency virus type 1 useslipid raft-co-localized CD4 and chemokine receptors for productive entryinto CD4+ T cells). It should be particularly appreciated that the viruscontains two introduced mutations in the RT gene (K103N and Y181C,created by PCR mutagenesis) that render the virus highly resistant tocurrent non-nucleoside HIV-1 drugs. Virus stocks were generated bycotransfection of plasmid DNA encoding VSV-G with vectorpNL4-3Env(−)Luc(+) into 293T cells. Sixty-four hours after transfection,virus-containing medium was collected by centrifugation and storedfrozen at −80° C.

HeLa cells were infected with the VSV-G pseudotyped virus in thepresence of screening compounds in a 384-well microtiter plate format.Forty-eight hours after initial infection, lysis buffer and LuciferaseAssay Reagent (Promega) was added to the cells and luciferase activitywas determined by counting the resultant luminescence using a LJLluminometer. Since the luciferase gene is carried in the virus genome,its expression level directly reflects the virus replication level inthe presence of a compound.

To evaluate the activity of the compounds against wild type HIV-1, theHeLa-JC53 cell line that expresses high levels of CD4 and CCR5 (seee.g., Platt et al. in Journal of Virology (1998), 72: 2855-2864: Effectof CCR5 and CD4 cell surface concentrations on infection bymacrophagetropic isolates of human immunodeficiency virus type 1) wasmodified by isolation of a stable cell line that expresses luciferaseunder the control of the HIV-1 promoter (long terminal repeat, i.e.,LTR). HIV-1 infection of this cell line stimulates the transcription ofluciferase from the HIV-1 promoter and the luciferase gene expressionlevel is proportional to the level of virus replication (Harrington etal. in Journal of Virology Methods (2000), 88: 111-115: Direct detectionof infection of HIV-1 in blood using a centrifugation-indicator cellassay; and Roos et al. in Virology (2000), 273: 307-315: LuSIV cells: areporter cell line for the detection and quantitation of a single cycleof HIV and SIV replication). Procedures for virus infection, compoundtesting and luciferase activity determination were the same as for theVSV-G pseudotyped HIV-1.

Two approaches were used to evaluate the cytotoxicity of the positivecompounds discovered in the HIV-1 virus assays. The first approachemployed another modified HeLa-JC53 cell line that constitutivelyexpresses high level of luciferase without virus infection. The level ofluciferase expression in these cells served as an indicator for cellreplication in the presence of the compounds. Procedures for compoundtesting and luciferase activity determination were the same as for thevirus infection tests. The other toxicity assay utilized HeLe-JC53 cellsand a commercially available MTS assay kit (Promega) that measures themitochondria function of the cells.

Results

The results are listed below 1 as EC₅₀ (nM) and IC₅₀ (nM). Table legend:A is <10, B is between 10 and 100, C is >100, ND is not determined Notethat many compounds of this invention exhibit activities on wild-type(WT) and resistant mutants below 10 nM.

EC₅₀ EC₅₀ EC₅₀ EC₅₀ WT Y181C Y188L L100I-K103N Cpd Structure (nM) (nM)(nM) (nM) 1

A A A B 2

A B C C 3

A B A A 4

A B B B 5

B C C C 6

B B B B 7

A A A B 8

A B B ND 9

A A A AContemplated Compounds and Prophetic Examples

In addition to the examples listed above, this invention provides orcontemplates many compounds, examples of which are shown in the tablesthat follow.

TABLE 1 Contemplated Compounds of Formula IA-1 IA-1

Ar Z  1. o,o′-diCH₃O-p-(CH═CHCN)phenyl CH₃  2.o,o′-diCH₃O-p-(CH═CHCN)phenyl H  3. o,o′-diCH₃O-p-(CH═CHCN)phenyl Br  4.o,o′-diCH₃O-p-(CH═CHCN)phenyl CH₂CH₃  5. o,o′-diCH₃O-p-(CH═CHCN)phenylisopropyl  6. o,o′-diCH₃O-p-(CH═CHCN)phenyl cyclopropyl  7.o,o′-diCH₃O-p-(CH═CHCN)phenyl F  8. o,o′-diCH₃O-p-(CH═CHCN)phenyl Cl  9.o,o′-diCH₃O-p-(CH═CHCN)phenyl CF₃  10. o,o′-diCH₃O-p-(CH═CHCN)phenylOCH₃  11. o,o′-diCH₃-p-(CH═CHCN)phenyl CH₃  12.o,o′-diCH₃-p-(CH═CHCN)phenyl H  13. o,o′-diCH₃-p-(CH═CHCN)phenyl Br  14.o,o′-diCH₃-p-(CH═CHCN)phenyl CH₂CH₃  15. o,o′-diCH₃-p-(CH═CHCN)phenylisopropyl  16. o,o′-diCH₃-p-(CH═CHCN)phenyl cyclopropyl  17.o,o′-diCH₃-p-(CH═CHCN)phenyl F  18. o,o′-diCH₃-p-(CH═CHCN)phenyl Cl  19.o,o′-diCH₃-p-(CH═CHCN)phenyl CF₃  20. o,o′-diCH₃-p-(CH═CHCN)phenyl OCH₃ 21. o,o′-di-CH₃O-p-CN-phenyl CH₃  22. o,o′-di-CH₃O-p-CN-phenyl H  23.o,o′-di-CH₃O-p-CN-phenyl Br  24. o,o′-di-CH₃O-p-CN-phenyl CH₂CH₃  25.o,o′-di-CH₃O-p-CN-phenyl isopropyl  26. o,o′-di-CH₃O-p-CN-phenylcyclopropyl  27. o,o′-di-CH₃O-p-CN-phenyl F  28.o,o′-di-CH₃O-p-CN-phenyl Cl  29. o,o′-di-CH₃O-p-CN-phenyl CF₃  30.o,o′-di-CH₃O-p-CN-phenyl OCH₃  31. 4-cyclopropylnaphth-1-yl CH₃  32.4-cyclopropylnaphth-1-yl H  33. 4-cyclopropylnaphth-1-yl Br  34.4-cyclopropylnaphth-1-yl CH₂CH₃  35. 4-cyclopropylnaphth-1-yl isopropyl 36. 4-cyclopropylnaphth-1-yl cyclopropyl  37. 4-cyclopropylnaphth-1-ylF  38. 4-cyclopropylnaphth-1-yl Cl  39. 4-cyclopropylnaphth-1-yl CF₃ 40. 4-cyclopropylnaphth-1-yl OCH₃  41. 2-CH₃-4-cyclopropylnaphth-1-ylCH₃  42. 2-CH₃-4-cyclopropylnaphth-1-yl H  43.2-CH₃-4-cyclopropylnaphth-1-yl Br  44. 2-CH₃-4-cyclopropylnaphth-1-ylCH₂CH₃  45. 2-CH₃-4-cyclopropylnaphth-1-yl isopropyl  46.2-CH₃-4-cyclopropylnaphth-1-yl cyclopropyl  47.2-CH₃-4-cyclopropylnaphth-1-yl F  48. 2-CH₃-4-cyclopropylnaphth-1-yl Cl 49. 2-CH₃-4-cyclopropylnaphth-1-yl CF₃  50.2-CH₃-4-cyclopropylnaphth-1-yl OCH₃  51. o,o′-di-CH₃-p-CN-phenyl CH₃ 52. o,o′-di-CH₃-p-CN-phenyl H  53. o,o′-di-CH₃-p-CN-phenyl Br  54.o,o′-di-CH₃-p-CN-phenyl CH₂CH₃  55. o,o′-di-CH₃-p-CN-phenyl isopropyl 56. o,o′-di-CH₃-p-CN-phenyl cyclopropyl  57. o,o′-di-CH₃-p-CN-phenyl F 58. o,o′-di-CH₃-p-CN-phenyl Cl  59. o,o′-di-CH₃-p-CN-phenyl CF₃  60.o,o′-di-CH₃-p-CN-phenyl OCH₃  61. 2,4,6-trimethyl phenyl CH₃  62.2,4,6-trimethyl phenyl H  63. 2,4,6-trimethyl phenyl Br  64.2,4,6-trimethyl phenyl CH₂CH₃  65. 2,4,6-trimethyl phenyl isopropyl  66.2,4,6-trimethyl phenyl cyclopropyl  67. 2,4,6-trimethyl phenyl F  68.2,4,6-trimethyl phenyl Cl  69. 2,4,6-trimethyl phenyl CF₃  70.2,4,6-trimethyl phenyl OCH₃  71. 2-CH₃-4-cyclopropyl phenyl CH₃  72.2-CH₃-4-cyclopropyl phenyl H  73. 2-CH₃-4-cyclopropyl phenyl Br  74.2-CH₃-4-cyclopropyl phenyl CH₂CH₃  75. 2-CH₃-4-cyclopropyl phenylisopropyl  76. 2-CH₃-4-cyclopropyl phenyl cyclopropyl  77.2-CH₃-4-cyclopropyl phenyl F  78. 2-CH₃-4-cyclopropyl phenyl Cl  79.2-CH₃-4-cyclopropyl phenyl CF₃  80. 2-CH₃-4-cyclopropyl phenyl OCH₃  81.2-Cl-4-cyclopropyl phenyl CH₃  82. 2-Cl-4-cyclopropyl phenyl H  83.2-Cl-4-cyclopropyl phenyl Br  84. 2-Cl-4-cyclopropyl phenyl CH₂CH₃  85.2-Cl-4-cyclopropyl phenyl isopropyl  86. 2-Cl-4-cyclopropyl phenylcyclopropyl  87. 2-Cl-4-cyclopropyl phenyl F  88. 2-Cl-4-cyclopropylphenyl Cl  89. 2-Cl-4-cyclopropyl phenyl CF₃  90. 2-Cl-4-cyclopropylphenyl OCH₃  91. 2,6-di-CH₃-4-cyclopropyl phenyl CH₃  92.2,6-di-CH₃-4-cyclopropyl phenyl H  93. 2,6-di-CH₃-4-cyclopropyl phenylBr  94. 2,6-di-CH₃-4-cyclopropyl phenyl CH₂CH₃  95.2,6-di-CH₃-4-cyclopropyl phenyl isopropyl  96. 2,6-di-CH₃-4-cyclopropylphenyl cyclopropyl  97. 2,6-di-CH₃-4-cyclopropyl phenyl F  98.2,6-di-CH₃-4-cyclopropyl phenyl Cl  99. 2,6-di-CH₃e-4-cyclopropyl phenylCF₃ 100. 2,6-di-CH₃-4-cyclopropyl phenyl OCH₃ 101.o,o′-di-CH₃-p-acetyl-phenyl CH₃ 102. o,o′-di-CH₃-p-acetyl-phenyl H 103.o,o′-di-CH₃-p-acetyl-phenyl Br 104. o,o′-di-CH₃-p-acetyl-phenyl CH₂CH₃105. o,o′-di-CH₃-p-acetyl-phenyl isopropyl 106.o,o′-di-CH₃-p-acetyl-phenyl cyclopropyl 107. o,o′-di-CH₃-p-acetyl-phenylF 108. o,o′-di-CH₃-p-acetyl-phenyl Cl 109. o,o′-di-CH₃-p-acetyl-phenylCF₃ 110. o,o′-di-CH₃-p-acetyl-phenyl OCH₃

TABLE 2 Contemplated Compounds of Formula IA-2 IA-2

Ar W 111. o,o′-diCH₃O-p-(CH═CHCN)phenyl CH₃ 112.o,o′-diCH₃O-p-(CH═CHCN)phenyl H 113. o,o′-diCH₃O-p-(CH═CHCN)phenyl Br114. o,o′-diCH₃O-p-(CH═CHCN)phenyl CH₂CH₃ 115.o,o′-diCH₃O-p-(CH═CHCN)phenyl isopropyl 116.o,o′-diCH₃O-p-(CH═CHCN)phenyl cyclopropyl 117.o,o′-diCH₃O-p-(CH═CHCN)phenyl F 118. o,o′-diCH₃O-p-(CH═CHCN)phenyl Cl119. o,o′-diCH₃O-p-(CH═CHCN)phenyl CF₃ 120.o,o′-diCH₃O-p-(CH═CHCN)phenyl OCH₃ 121. o,o′-diCH₃-p-(CH═CHCN)phenyl CH₃122. o,o′-diCH₃-p-(CH═CHCN)phenyl H 123. o,o′-diCH₃-p-(CH═CHCN)phenyl Br124. o,o′-diCH₃-p-(CH═CHCN)phenyl CH₂CH₃ 125.o,o′-diCH₃-p-(CH═CHCN)phenyl isopropyl 126. o,o′-diCH₃-p-(CH═CHCN)phenylcyclopropyl 127. o,o′-diCH₃-p-(CH═CHCN)phenyl F 128.o,o′-diCH₃-p-(CH═CHCN)phenyl Cl 129. o,o′-diCH₃-p-(CH═CHCN)phenyl CF₃130. o,o′-diCH₃-p-(CH═CHCN)phenyl OCH₃ 131. o,o′-di-CH₃O-p-CN-phenyl CH₃132. o,o′-di-CH₃O-p-CN-phenyl H 133. o,o′-di-CH₃O-p-CN-phenyl Br 134.o,o′-di-CH₃O-p-CN-phenyl CH₂CH₃ 135. o,o′-di-CH₃O-p-CN-phenyl isopropyl136. o,o′-di-CH₃O-p-CN-phenyl cyclopropyl 137. o,o′-di-CH₃O-p-CN-phenylF 138. o,o′-di-CH₃O-p-CN-phenyl Cl 139. o,o′-di-CH₃O-p-CN-phenyl CF₃140. o,o′-di-CH₃O-p-CN-phenyl OCH₃ 141. 4-cyclopropylnaphth-1-yl CH₃142. 4-cyclopropylnaphth-1-yl H 143. 4-cyclopropylnaphth-1-yl Br 144.4-cyclopropylnaphth-1-yl CH₂CH₃ 145. 4-cyclopropylnaphth-1-yl isopropyl146. 4-cyclopropylnaphth-1-yl cyclopropyl 147. 4-cyclopropylnaphth-1-ylF 148. 4-cyclopropylnaphth-1-yl Cl 149. 4-cyclopropylnaphth-1-yl CF₃150. 4-cyclopropylnaphth-1-yl OCH₃ 151. 2-CH₃-4-cyclopropylnaphth-1-ylCH₃ 152. 2-CH₃-4-cyclopropylnaphth-1-yl H 153.2-CH₃-4-cyclopropylnaphth-1-yl Br 154. 2-CH₃-4-cyclopropylnaphth-1-ylCH₂CH₃ 155. 2-CH₃-4-cyclopropylnaphth-1-yl isopropyl 156.2-CH₃-4-cyclopropylnaphth-1-yl cyclopropyl 157.2-CH₃-4-cyclopropylnaphth-1-yl F 158. 2-CH₃-4-cyclopropylnaphth-1-yl Cl159. 2-CH₃-4-cyclopropylnaphth-1-yl CF₃ 160.2-CH₃-4-cyclopropylnaphth-1-yl OCH₃ 161. o,o′-di-CH₃-p-CN-phenyl CH₃162. o,o′-di-CH₃-p-CN-phenyl H 163. o,o′-di-CH₃-p-CN-phenyl Br 164.o,o′-di-CH₃-p-CN-phenyl CH₂CH₃ 165. o,o′-di-CH₃-p-CN-phenyl isopropyl166. o,o′-di-CH₃-p-CN-phenyl cyclopropyl 167. o,o′-di-CH₃-p-CN-phenyl F168. o,o′-di-CH₃-p-CN-phenyl Cl 169. o,o′-di-CH₃-p-CN-phenyl CF₃ 170.o,o′-di-CH₃-p-CN-phenyl OCH₃ 171. 2,4,6-trimethyl phenyl CH₃ 172.2,4,6-trimethyl phenyl H 173. 2,4,6-trimethyl phenyl Br 174.2,4,6-trimethyl phenyl CH₂CH₃ 175. 2,4,6-trimethyl phenyl isopropyl 176.2,4,6-trimethyl phenyl cyclopropyl 177. 2,4,6-trimethyl phenyl F 178.2,4,6-trimethyl phenyl Cl 179. 2,4,6-trimethyl phenyl CF₃ 180.2,4,6-trimethyl phenyl OCH₃ 181. 2-CH₃-4-cyclopropyl phenyl CH₃ 182.2-CH₃-4-cyclopropyl phenyl H 183. 2-CH₃-4-cyclopropyl phenyl Br 184.2-CH₃-4-cyclopropyl phenyl CH₂CH₃ 185. 2-CH₃-4-cyclopropyl phenylisopropyl 186. 2-CH₃-4-cyclopropyl phenyl cyclopropyl 187.2-CH₃-4-cyclopropyl phenyl F 188. 2-CH₃-4-cyclopropyl phenyl Cl 189.2-CH₃-4-cyclopropyl phenyl CF₃ 190. 2-CH₃-4-cyclopropyl phenyl OCH₃ 191.2-Cl-4-cyclopropyl phenyl CH₃ 192. 2-Cl-4-cyclopropyl phenyl H 193.2-Cl-4-cyclopropyl phenyl Br 194. 2-Cl-4-cyclopropyl phenyl CH₂CH₃ 195.2-Cl-4-cyclopropyl phenyl isopropyl 196. 2-Cl-4-cyclopropyl phenylcyclopropyl 197. 2-Cl-4-cyclopropyl phenyl F 198. 2-Cl-4-cyclopropylphenyl Cl 199. 2-Cl-4-cyclopropyl phenyl CF₃ 200. 2-Cl-4-cyclopropylphenyl OCH₃ 201. 2,6-di-CH₃-4-cyclopropyl phenyl CH₃ 202.2,6-di-CH₃-4-cyclopropyl phenyl H 203. 2,6-di-CH₃-4-cyclopropyl phenylBr 204. 2,6-di-CH₃-4-cyclopropyl phenyl CH₂CH₃ 205.2,6-di-CH₃-4-cyclopropyl phenyl isopropyl 206. 2,6-di-CH₃-4-cyclopropylphenyl cyclopropyl 207. 2,6-di-CH₃-4-cyclopropyl phenyl F 208.2,6-di-CH₃-4-cyclopropyl phenyl Cl 209. 2,6-di-CH₃4-cyclopropyl phenylCF₃ 210. 2,6-di-CH₃-4-cyclopropyl phenyl OCH₃ 211.o,o′-di-CH₃-p-acetyl-phenyl CH₃ 212. o,o′-di-CH₃-p-acetyl-phenyl H 213.o,o′-di-CH₃-p-acetyl-phenyl Br 214. o,o′-di-CH₃-p-acetyl-phenyl CH₂CH₃215. o,o′-di-CH₃-p-acetyl-phenyl isopropyl 216.o,o′-di-CH₃-p-acetyl-phenyl cyclopropyl 217. o,o′-di-CH₃-p-acetyl-phenylF 218. o,o′-di-CH₃-p-acetyl-phenyl Cl 219. o,o′-di-CH₃-p-acetyl-phenylCF₃ 220. o,o′-di-CH₃-p-acetyl-phenyl OCH₃

1. A compound of formula

wherein: the dashed line represents a double bond located between C(V)and D; A is S; D is C(W); T is NH, O, or S; W is H, F, Cl, Br, C₁-C₆alkyl, C₂-C₆ alkenyl, OC₁-C₆ alkyl, C₃-C₆ cycloalkyl, OC₃-C₆ cycloalkyl,phenyl or benzyl; wherein the alkyl, alkenyl, cycloalkyl, phenyl groupsand the phenyl moiety of the benzyl group are optionally substitutedwith 1-3 groups selected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃alkyl; V is H, halogen, or C₁-C₆ alkyl; Ar is selected from (a), (b),(c), and (d) below:

wherein: each R^(P) is selected from methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, C₃-C₆ cycloalkyl, cyano, CH═CHCN, Cl, Br, I, acetyl,and C₁-C₆ alkyl-NH; R⁴, R⁵, and R⁶ are independently selected from H, F,Cl, Br, CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,NH₂ and NHCH₃; or R⁶ and R^(P) on adjacent ring atoms, together with thering atoms to which they are attached, form an additional fusedfive-membered ring; Q and Q′ are independently selected from N and CH;R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, orcyclobutyl; and R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, H or CH₃;or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein Ar is (a) or (c).
 3. The compound of claim 2, wherein R⁶ is Hor a substituent in the 2-position.
 4. The compound of claim 3, whereinAr is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethyl phenyl;4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-1-naphthyl;4-cyclopropyl-1-naphthyl; 2,6-dimethyl-4-cyanophenyl;2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl;2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl;2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropylphenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.
 5. Thecompound of claim 1, which is a compound of formula IA-2:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, which is a compound of formula IA-4:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim5 or claim 6, wherein Ar is

wherein R⁶ is selected from H, F, Cl, Br, CH₃, CF₃, CH₂F, CHF₂,isopropyl, cyclopropyl, OCH₃, OH, OCF₃, NH₂ and NHCH₃; R⁷ is Cl, Br, I,CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and G iscyclopropyl, acetyl, methyl, bromo, or cyano.
 8. The compound of claim7, wherein V is H; and W is H, methyl, F, Cl, or Br.
 9. The compound ofclaim 3 which is a compound of formula IA-2a:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim9, wherein V is H; and W is H, F, Cl, Br, methyl, ethyl, or benzyl. 11.The compound of claim 10, wherein W is H, F, Cl, Br, or methyl.
 12. Thecompound of claim 9, wherein V is H; R⁶ is methyl, methoxy or chloro;and R⁷ is 6-methyl, or 6-methoxy.
 13. The compound of claim 12, whereinR^(P) is CN, cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.
 14. Acompound of formula IB:

wherein: the dashed line represents a double bond located between C(V)and D; A is S; D is C(W); W is H, F, Cl, Br, C1-C6 alkyl, C2-C6 alkenyl,OC1-C6 alkyl, C3-C6 cycloalkyl, OC₃-C₆ cycloalkyl, phenyl or benzyl;wherein the alkyl, alkenyl, cycloalkyl, phenyl groups and the phenylmoiety of the benzyl group are optionally substituted with 1-3 groupsselected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃ alkyl; V is H,halogen or C₁-C₆ alkyl; Ar is selected from (a), (b), (c), and (d)below:

wherein each R^(P) is selected from methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, C₃-C₆ cycloalkyl, cyano, CH═CHCN, Cl, Br, I, acetyl,and C₁-C₆ alkyl-NH; R⁴, R⁵, and R⁶ are independently selected from H, F,Cl, Br, CH₃, CF₃,CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,NH₂, and NHCH₃; or R⁶ and R^(P) on adjacent ring atoms, together withthe ring atoms to which they are attached, form an additional fusedfive-membered ring; Q and Q′ are independently selected from N and CH;R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, orcyclobutyl; and R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, H or CH₃;or a pharmaceutically acceptable salt thereof.
 15. The compound of claim14 which is a compound of formula IB-1:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15, wherein V is H; R⁶ is 2-methyl, 2-methoxy, or 2-chloro; and R⁷ is6-methyl, or 6-methoxy.
 17. The compound of claim 16, wherein R^(P) isCN, cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.
 18. Apharmaceutical composition comprising a compound of formula I:

wherein: the dashed line represents a double bond located between C(V)and D; A is S; D is C(W); T is NH, O, or S; W is H, F, Cl, Br, C1-C6alkyl, C2-C6 alkenyl, OC1-C6 alkyl, C3-C6 cycloalkyl, OC₃-C₆ cycloalkyl,phenyl or benzyl; wherein the alkyl, alkenyl, cycloalkyl, phenyl groupsand the phenyl moiety of the benzyl group are optionally substitutedwith 1-3 groups selected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃alkyl; V is H, halogen, or C₁-C₆ alkyl; Ar is selected from (a), (b),(c), and (d) below:

wherein each R^(P) is selected from methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, C₃-C₆ cycloalkyl, cyano, CH═CHCN, Cl, Br, I, acetyl,and C₁-C₆ alkyl-NH; R⁴, R⁵, and R⁶ are independently selected from H, F,Cl, Br, CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,NH₂ and NHCH₃; or R⁶ and R^(P) on adjacent ring atoms, together with thering atoms to which they are attached, form an additional fusedfive-membered ring; Q and Q′ are independently selected from N and CH;and R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, orcyclobutyl; and R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, H or CH₃;or a pharmaceutically acceptable salt thereof.
 19. A method ofinhibiting a human immunodeficiency virus (HIV) comprising contactingsaid immunodeficiency virus with a compound of formula I, or apharmaceutically acceptable salt thereof:

wherein: the dashed line represents a double bond located between C(V)and D; A is S; D is C(W); T is NH, O, or S; W is H, F, Cl, Br, C₁-C₆alkyl, C₂-C₆ alkenyl, OC₁-C₆ alkyl, C₃-C₆ cycloalkyl, OC₃-C₆ cycloalkyl,phenyl or benzyl; wherein the alkyl, alkenyl, cycloalkyl, phenyl groupsand the phenyl moiety of the benzyl group are optionally substitutedwith 1-3 groups selected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃alkyl; V is H, halogen, or C₁-C₆ alkyl; Ar is selected from (a), (b),(c), and (d) below:

wherein each R^(P) is selected from methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, C₃-C₆ cycloalkyl, cyano, CH═CHCN, Cl, Br, I, acetyl,and C₁-C₆ alkyl-NH; R⁴, R⁵, and R⁶ are independently selected from H, F,Cl, Br, CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,NH₂ and NHCH₃; or R⁶ and R^(P) on adjacent ring atoms, together with thering atoms to which they are attached, form an additional fusedfive-membered ring; Q and Q′ are independently selected from N and CH;R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, orcyclobutyl; and R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, H or CH₃.20. The method of claim 19, wherein said contacting occurs within acell.
 21. A method for treating a human immunodeficiency virus (HIV)infection in a subject, wherein the treating of a human immunodeficiencyvirus (HIV) infection is alleviating, ameliorating, or inhibiting thehuman immunodeficiency virus (HIV) infection, the method comprisingadministering to the subject a pharmaceutically effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof:

wherein: the dashed line represents a double bond located between C(V)and D; A is S; D is C(W); T is NH, O, or S; W is H, F, Cl, Br, C₁-C₆alkyl, C₂-C₆ alkenyl, OC₁-C₆ alkyl, C₃-C₆ cycloalkyl, OC₃-C₆ cycloalkyl,phenyl or benzyl; wherein the alkyl, alkenyl, cycloalkyl, phenyl groupsand the phenyl moiety of the benzyl group are optionally substitutedwith 1-3 groups selected from halogen, CF₃, C₁-C₃ alkyl, and OC₁-C₃alkyl; V is H, halogen, or C₁-C₆ alkyl; Ar is selected from (a), (b),(c), and (d) below:

wherein each R^(P) is selected from methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, C₃-C₆ cycloalkyl, cyano, CH═CHCN, Cl, Br, I, acetyl,and C₁-C₆ alkyl-NH; R⁴, R⁵, and R⁶ are independently selected from H, F,Cl, Br, CH₃, CF₃, CH₂F, CHF₂, isopropyl, cyclopropyl, OCH₃, OH, OCF₃,NH₂ and NHCH₃; or R⁶ and R^(P) on adjacent ring atoms, together with thering atoms to which they are attached, form an additional fusedfive-membered ring; Q and Q′ are independently selected from N and CH;R⁷ is Cl, Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, orcyclobutyl; and R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, H or CH₃.22. The method of claim 21 wherein said human immunodeficiency virus(HIV) is a drug resistant mutant.
 23. The method of claim 21 whereinsaid human immunodeficiency virus (HIV) is resistant to non-nucleosidereverse transcriptase inhibitors.
 24. The method of claim 21 furthercomprising administering at least one HIV or AIDS drug.
 25. The methodof claim 21, wherein Ar is (a) or (c).
 26. The method of claim 25,wherein R⁶ is H or a substituent in the 2-position.
 27. The method ofclaim 26, wherein Ar is selected from 4-cyclopropyl phenyl;4-cyclopropylmethyl phenyl; 4-bromophenyl; 2-chloro-4-bromophenyl;4-bromo-1-naphthyl; 4-cyclopropyl-1-naphthyl;2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl;2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl)phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropylphenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethylphenyl; and 2,6-dimethyl-4-acetyl phenyl.
 28. The method of claim 21,wherein the compound is a compound of formula IA-2 or formula IA-4:

or a pharmaceutically acceptable salt thereof.
 29. The method of claim28, wherein Ar is

wherein R⁶ is selected from H, F, Cl, Br, CH₃, CF₃, CH₂F, CHF₂,isopropyl, cyclopropyl, OCH₃, OH, OCF₃, NH₂ and NHCH₃; R⁷ is from Cl,Br, I, CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, or cyclobutyl;and G is cyclopropyl, acetyl, methyl, bromo, or cyano.
 30. The method ofclaim 29, wherein V is H; and W is H, methyl, F, Cl, or Br.
 31. Themethod of claim 21, wherein the compound is a compound of formula IA-2a:

or a pharmaceutically acceptable salt thereof.
 32. The method of claim21, wherein the compound is a compound of formula IB:

or a pharmaceutically acceptable salt thereof.
 33. The method of claim21, wherein the compound is a compound of formula IB-1:

or a pharmaceutically acceptable salt thereof.
 34. The method of claim33, wherein V is H; R⁶ is 2-methyl, 2-methoxy, or 2-chloro; and R⁷ is6-methyl, or 6-methoxy.
 35. The method of claim 34, wherein R^(P) is CN,cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.
 36. The method of claim19, wherein Ar is (a) or (c).
 37. The method of claim 36, wherein R⁶ isH or a substituent in the 2-position.
 38. The method of claim 37,wherein Ar is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethylphenyl; 4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-1-naphthyl;4-cyclopropyl-1 -naphthyl; 2,6-dimethyl-4-cyanophenyl;2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl;2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl;2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropylphenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl. 39.The method of claim 19, wherein the compound is a compound of formulaIA-2 or formula IA-4:

or a pharmaceutically acceptable salt thereof.
 40. The method of claim39, wherein Ar is

wherein: R⁶ is selected from H, F, Cl, Br, CH₃, CF₃, CH₂F, CHF₂,isopropyl, cyclopropyl, OCH₃, OH, OCF₃, NH₂ and NHCH₃; R⁷ is Cl, Br, I,CH₃, CF₃, OCH₃, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and G iscyclopropyl, acetyl, methyl, bromo, or cyano.
 41. The compound of claim40, wherein V is H; and W is H, methyl, F, Cl, or Br.
 42. The method ofclaim 19, wherein the compound is a compound of formula IA-2a:

or a pharmaceutically acceptable salt thereof.
 43. The method of claim19, wherein the compound is a compound of formula IB:

or a pharmaceutically acceptable salt thereof.
 44. The method of claim43, wherein the compound is a compound of formula IB-1:

or a pharmaceutically acceptable salt thereof.
 45. The method of claim44, wherein V is H; R⁶ is 2-methyl, 2-methoxy, or 2-chloro; and R⁷ is6-methyl, or 6-methoxy.
 46. The method of claim 45, wherein R^(P) is CN,cyclopropyl, methyl, Br, Cl, CH═CHCN, or acetyl.